Indenyl compounds, pharmaceutical compositions, and medical uses thereof

ABSTRACT

Disclosed are compounds, for example, compounds of formula I, 
                         
wherein R, R 0 , R 1 -R 8 , n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition, for example, cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 15/537,292, filed Jun. 16, 2017 as the U.S. national phase ofPCT/US2015/066146, filed Dec. 16, 2015, claiming the benefit of U.S.patent application Ser. No. 14/571,647, filed Dec. 16, 2014, thedisclosures of which are incorporated herein by reference in theirentireties for all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

This invention was made with partial support under NIH/NCI Grant NumbersCA 155638 and CA 148817. Therefore, the U.S. Government has certainrights in this invention.

BACKGROUND OF THE INVENTION

Cancer is a leading cause of death in the developed world, with over onemillion people diagnosed and more than 500,000 deaths per year in theUnited States alone. Overall it is estimated that at least one in threepeople will develop some form of cancer during their lifetime. There aremore than 200 different histopathological types of cancer, four of which(breast, lung, colorectal, and prostate) account for over half of allnew cases in the U.S. (Jemal et al., Cancer J. Clin., 53, 5-26 (2003)).

Many of these tumors arise from mutations that activate Ras proteins,which control critically important cellular signaling pathways thatregulate growth and other processes associated with tumorigenesis. Thename “Ras” is an abbreviation of “Rat sarcoma” reflecting the way thefirst members of the Ras protein family were discovered. The name “ras”also is used to refer to the family of genes encoding these proteins.

Ras-driven cancers have remained the most intractable diseases to anyavailable treatment. New therapeutic and preventative strategies areurgently needed for such cancers (Stephen et al., Cancer Cell, 25,272-281 (2014)). Drug discovery programs worldwide have soughtRas-selective drugs for many years, but heretofore no avail (Spiegel, etal., Nature Chem. Biol., 10, 613-622 (2014)). New drugs that selectivelytarget abnormal or mutant Ras and/or Ras-mediated pathological processesin patients' tumors will enable highly efficacious treatments of suchpatients while minimizing toxicity to cells and tissues with normal Rasfunctions (Stephen et al., supra; Spiegel et al., supra).

Ras proteins are key regulators of several aspects of normal cell growthand malignant transformation, including cellular proliferation, survivaland invasiveness, tumor angiogenesis and metastasis (Downward, NatureRev. Cancer, 3, 11-22 (2003)). Ras proteins are abnormally active inmost human tumors due to mutations in the ras genes themselves, or inupstream or downstream Ras pathway components, or other alterations inRas signaling. Targeted therapies that inhibit Ras-mediated pathwaystherefore are expected to inhibit the growth, proliferation, survivaland spread of tumor cells having activated or mutant Ras. Some such newexperimental therapeutic agents have shown promising activity inpreclinical studies, albeit with only modest activity in human clinicaltrials.

Genetic mutations in ras genes were first identified in human cancerover 3 decades ago. Such mutations result in the activation of one ormore of three major Ras protein isoforms, including H-Ras, N-Ras, orK-Ras, that turn on signaling pathways leading to uncontrolled cellgrowth and tumor development. Activating ras gene mutations occur denovo in approximately one third of all human cancers and are especiallyprevalent in pancreatic, colorectal, and lung tumors. Ras mutations alsodevelop in tumors that become resistant to chemotherapy and/orradiation, as well as to targeted therapies, such as receptor tyrosinekinase inhibitors (Gysin et al., Genes Cancer, 2, 359-372 (2011)). Whileras mutations are relatively infrequent in other tumor types, forexample, breast cancer, Ras can be pathologically activated by certaingrowth factor receptors that signal through Ras.

Although ras gene mutations have been known for many years, therecurrently are no available cancer therapeutics approved by the U.S. Foodand Drug Administration that are known to selectively suppress thegrowth of tumors driven by activated Ras. In fact, Ras has beendescribed as “undruggable” because of the relative abundance in cellsand high affinity for its substrate, GTP (Takashima and Faller, ExpertOpin. Ther. Targets, 17, 507-531 (2013)).

In addition to its role in cancer, activated Ras is important in avariety of other diseases, collectively referred to as “rasopathies.”One such disease, neurofibromatosis type 1 (NF1), a very prevalentautosomal dominant heritable disease, is caused by a mutation inneurofibromin, a Ras GAP (inactivating protein), which results in Rashyperactivation in the relatively common event of loss of the second NF1allele. Such mutations reportedly affect 1:3000 live births. The mostdire symptoms associated with NF1 include numerous benign tumors(neurofibromas) arising from precursor nerve cells and Schwann cells ofthe peripheral nervous system. These tumors can cause severe problemsdepending on their location within the body, such as hearing or visionloss, as well as disfiguring masses on visible areas. Less common butextremely serious complications may arise when central nervous systemgliomas develop or plexiform neurofibromas become transformed, resultingin the development of metastatic peripheral nerve sheath tumors (Tidymanand Rauen, Curr. Opin. Genet. Dev., 19, 230-236 (2009)). Another raredevelopmental disease which is attributable to hyperactive H-Ras isCostello syndrome. This condition causes a range of developmentalabnormalities as well as predisposing patients to a variety of benignand malignant neoplasms (Tidyman and Rauen, supra).

Several approaches to treat diseases that arise from activating rasmutations have been undertaken. Because full maturation of the Rasprotein requires lipid modification, attempts have been made to targetthis enzymatic process with inhibitors of farnesyl transferase andgeranylgeranyltransferase, but with limited success and significanttoxicity. Targeting of downstream components of Ras signaling withinhibitors of Raf/Mek/Erk kinase components of the cascading pathway hasbeen an extremely active area of pharmaceutical research, but alsofraught with difficulties and paradoxes arising from complex feedbacksystems within the pathways (Takashima and Faller, supra).

Inhibitors targeting components within the PI3K/Akt pathway also havenot been successful as single agents, but presumably might synergizewith Raf/Mek/Erk pathway inhibitors to block Ras-dependent tumor growthand survival. Similarly, several other molecular targets have beenidentified from RNAi screening, which might provide new opportunities toinhibit the growth of Ras-driven tumors; such other potential targetsinclude CDK4, Cyclin D1, Tiaml, Myc, STK33, and TBK, as well as severalgenes involved in mitosis (Takashima and Faller, supra).

The nonsteroidal anti-inflammatory drug, sulindac (FIG. 1) has beenreported to selectively inhibit proliferation of cultured tumor cellshaving ras mutations (Herrmann et al., Oncogene, 17, 1769-1776 (1998)).Extensive chemical modifications of sulindac and the related NSAID,indomethacin, have been aimed at removing cyclooxygenase-inhibitoryactivity, while improving anticancer activity (Gurpinar et al., Mol.Cancer Ther., 12, 663-674 (2013); Romeiro et al., Eur. J. Med. Chem.,44, 1959-1971 (2009); Chennamaneni et al., Eur. J. Med. Chem., 56, 17-29(2012)). An example of a highly potent antiproliferative derivative is ahydroxy-substituted indene derivative of sulindac, OSIP-487703 (FIG. 1),that was reported to arrest colon cancer cells in mitosis by causingmicrotubule depolymerization (Xiao et al., Mol. Cancer Ther., 5, 60-67(2006)). OSIP-487703 also was reported to inhibit the growth and induceapoptosis of human SW480 colon cancer cells. These properties of mitoticarrest and microtubule disruption were shared by several additionalrelated compounds, including a pyridine (CP461) and trimethoxy (CP248)substituted variants (FIG. 1) (Lim et al., Clin. Cancer Res, 9,4972-4982 (2003); Yoon, et al., Mol. Cancer Ther., 1, 393-404 (2002)).However, there was no reported association of antitumor properties ofthese compounds (FIG. 1) with Ras function, but rather such propertieswere attributed to direct binding to the microtubule subunit, tubulin,thereby causing mitotic arrest and blocking cell division. Still otherreports describe their ability to induce apoptosis by inhibition of cGMPphosphodiesterase (Thompson et al., Cancer Research, 60, 3338-3342(2000)).

Other investigators reported that sulindac sulfide (FIG. 1) can inhibitRas-induced malignant transformation, possibly by decreasing the effectsof activated Ras on its main effector, the c-Raf-1kinase, due to directbinding to the ras gene product p21 in a non-covalent manner (Herrmannet al., supra). Sulindac sulfide also can inhibit focus formation, amarker of malignant transformation, by rat or mouse fibroblasts byforced Ras expression, but not by other transformation pathways (Gala etal., Cancer Lett., 175, 89-94 (2002); Herrmann et al., supra). Sulindacsulfide was reported also to bind Ras directly and interfere withnucleotide exchange. Several groups additionally reported that sulindacinterferes with Ras binding to the downstream signaling kinase c-Raf,and blocks activation of downstream signaling or transcription (Herrmannet al., supra; Pan et al., Cell Signal., 20, 1134-1141 (2008)).

The aforementioned findings led to efforts to improve the Ras inhibitoryactivity of sulindac sulfide through chemical modifications (Karaguni etal., Bioorg. Med. Chem. Lett., 12, 709-713 (2002)). Several derivativeswere identified that were more potent inhibitors of tumor cellproliferation, and four related compounds (FIG. 2) exhibited selectivitytowards a Ras-transfected MDCK cell line compared to the parental cellline. Three of these compounds also potently disrupted the Ras-Rafinteraction. However, none of the four were more potent toward themutant K-Ras-bearing SW-480 cell line, although they did inhibit Erkphosphorylation and bound weakly to the G-domain of H-Ras (Waldmann etal., Angew. Chem. Int. Ed. Engl., 43, 454-458 (2004)).

In addition to sulindac sulfide, the non-COX inhibitory sulfonemetabolite of sulindac has been reported to have selective effects ontumor cells with mutant Ras. For example, transfection of Caco-2 colontumor cells with the activated K-Ras oncogene caused cells treated witheither sulindac sulfide or sulfone to undergo apoptosis earlier thannon-transfected cells. (Lawson et al., Cancer Epidemiol. BiomarkersPrev., 9, 1155-62 (2000)). Other investigators have reported thatsulindac sulfone can inhibit mammary tumorigenesis in rats and that theeffect was greater on tumors with the mutant H-Ras genotype (Thompson etal., Cancer Research 57, 267-271 (1997)). However, other investigatorsreport that the inhibition of colon tumorigenesis in rats by eithersulindac or sulindac sulfone occurs independently of K-Ras mutations (deJong et al., Amer. J. Physio. Gastro and Liver Phys. 278, 266-272(2000)). Yet other investigators report that the K-Ras oncogeneincreases resistance to sulindac-induced apoptosis in rat enterocytes(Arber et al., Gastroenterology, 113, 1892-1900 (1997)). As such, theinfluence of Ras mutations on the anticancer activity of sulindac andits metabolites is controversial and unresolved, and has not beenexploited to improve anticancer potency or selectivity.

Certain other compounds have been described with selective toxicitytoward cells expressing activated Ras. A high-throughput phenotypicscreen of over 300,000 compounds was conducted within NIH MolecularLibraries Screening Center program to identify compounds which weresynthetically lethal to cells expressing oncogenic H-Ras. A leadcompound, ML210 (FIG. 3), inhibited growth of cells expressing mutantRas with an IC50 of 71 nM, and was 4-fold selective versus cells lackingoncogenic Ras. Though the specific molecular target of ML210 is unknown,the compound was chemically optimized to eliminate reactive groups andimprove pharmacologic properties (ML210, Dec. 12, 2011 update, ProbeReports from NIH Molecular Libraries Program, Bethesda,http://www.ncbi.nlm.nih.gov/books/NBK98919/).

A separate high-throughput screen identified two compounds, RSL3 andRSL5 (FIG. 3) which induce non-apoptotic, Mek-dependent, oxidative celldeath (Yang and Stockwell, Chem. Biol., 15, 234-245 (2008). RSL5, like apreviously identified Ras synthetic lethal compound, erastin (FIG. 3),binds the voltage-dependent anion channel (VDAC) (Dolma et al., CancerCell, 3, 285-296 (2003)). Yet another small-molecule screen identifiedoncrasin, a compound selectively active against K-Ras mutant cell lines(Guo et al., Cancer Res., 68, 7403-7408 (2008)). One analog, NSC-743380(FIG. 3), is highly potent and has shown anti-tumor activity in apreclinical model of K-Ras driven renal cancer (Guo et al., PLoS One, 6,e28487 (2011)). A prodrug approach has recently been described foroncrasin derivatives, to improve stability, pharmacokinetics, and safety(Wu et al., Bioorg. Med. Chem., 22, 5234-5240 (2014)). A syntheticlethal screen using embryonic fibroblasts derived from mice expressingthe oncogenic K-Ras (G12D) identified a compound, lanperisone (FIG. 3),that induced non-apoptotic cell death via a mechanism involvingoxidative stress (Shaw et al., Proc. Natl. Acad. Sci. USA, 108,8773-8778 (2011)). In contrast to the synthetic lethal approach, afragment-based screening approach paired with crystallographic studieshas been used to identify compounds which irreversibly bind to andinhibit K-Ras in lung tumor cells having the relatively rare G12C rasgene mutation (Ostrem et al., Nature, 503, 548-551 (2013)). Whilecompounds of this series potently inhibit Ras through a covalentinteraction, the low frequency of this mutation may limit the utility ofsuch compounds. Finally, a new investigational strategy for targetingoncogenic Ras has been described (Zimmerman et al., J. Med. Chem., 57,5435-5448 (2014)) which involves structure guided design and kineticanalysis of benzimidazole inhibitors targeting the PDE prenyl bindingsite.

WO 97/47303 and WO 2014/047592, U.S. Patent Application Publication Nos.2003/0009033 and 2003/0194750, U.S. Pat. Nos. 6,063,818; 6,071,934,5,965,619; 5,401,774; 6,538,029, 6,121,321, and UK Patent No. GB 1370028disclose certain anticancer compounds; however, these documents do notdisclose that the compounds have any Ras-specific activity, nor anybasis for a selective Ras-directed method of use.

The foregoing shows that there exists an unmet need for compounds thatare suitable for treating or preventing cancers. There further exists anunmet need for compounds that inhibit Ras-dependent diseases orundesirable conditions.

BRIEF SUMMARY OF THE INVENTION

The invention provides a compound of formula I:

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

R₁, R₂, R₃, and R₄ are independently selected from hydrogen, halogen,alkyl, cycloalkyl, haloalkyl, hydroxyl, carboxyl, alkoxy, formyloxy,hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl,dialkylamino, mercapto, alkylmercapto, cyano, cyanoalkyl, nitro, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, alkoxycarbonyl,alkylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy, andsulfonamido, or any two of R₁, R₂, R₃, and R₄ form an alkylenedioxygroup;

R₅, R₆, R₇, and R₈ are independently selected from hydrogen, alkyl,haloalkyl, and alkoxy; or R₅ and R₆ together form a carbon-carbon bond;

Y is hydrogen, alkyl, or haloalkyl, and Y′ is hydrogen, alkyl,haloalkyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, orhaloalkyl;

X is selected from hydrogen, alkyl, haloalkyl, alkoxy, alkylmercapto,and hydroxyl with the proviso that X is not hydroxyl when Y and Y′together is oxygen in a compound of formula I wherein R₅ and R₆ togetheris a carbon-carbon bond, or X is NR′R″, where R′ and R″ areindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryloxy, cyanoalkyl, haloalkyl, alkoxy, alkenyl, alkynyl,hydroxyalkyl, polyhydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminoalkyl, alkylamino, aryl, arylalkyl, arylalkenyl, arylcycloalkyl,arylcycloalkenyl, carbocyclyl, and carbocyclylalkyl where the carbocycleof the carbocyclyl and the carbocyclylalkyl is selected from 7-memberedcarbocyclic rings containing no double bond, or one, two or three doublebonds, 6-membered carbocyclic rings containing no double bond, or one,two or three double bonds, 5-membered carbocyclic rings containing nodouble bond, or one or two double bonds, 4-membered carbocyclic ringscontaining no double bond or one double bond and 3-membered carbocyclicrings containing no double bond, heterocyclyl, and heterocyclylalkyl,where the heterocycle of the heterocyclyl and heterocyclylalkyl isselected from 7-membered heterocyclic rings, 6-membered heterocyclicrings, and 5-membered heterocyclic rings, and the aryl of the aryl,arylalkyl, arylalkylenyl, arylcycloalkyl, or arylcycloalkenyl structureor the carbocyclic or heterocyclic structure is optionally substitutedwith one or more of halo, alkyl, haloalkyl, hydroxyl, alkoxy, amino,alkylamino, dialkylamino, mercapto, alkylmercapto, carboxamido,aldehydo, cyano, oxo, alkylcarbonyloxy, sulfonamido and COR₁₁, whereinR₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen and optionally oxygen or sulfur, and the heterocyclicring is optionally substituted with one or more of halo, alkyl,haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto,alkylmercapto, carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, andsulfonamido; and

E is a substituted or unsubstituted, saturated or unsaturated,7-membered, 6-membered, 5-membered, 4-membered or 3-membered carbocyclicor heterocyclic ring; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when E is a substituted aryl or heteroaryl, thenno substituent on the aryl or heteroaryl ring can be alkylsulfinyl oralkylsulfonyl, and no substituent on the aryl ring can be alkylmercapto,nor p-halo when R′ is dialkylaminoalkyl;

or, when R₅ and R₆ together is a carbon-carbon bond, R″ is hydrogen andR′ is a substituted arylalkyl, then E cannot be a substituted orunsubstituted heterocyclic ring selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, triazinyl, thiophenyl,furanyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, azinyl, tratrazolyl, pyridazinyl, and pyrrolyl;

or, when n is 1 or 2, R₅ and R₆ together form a carbon-carbon bond, Yand Y′ are hydrogens or Y and Y′ together is oxygen, and E is asubstituted phenyl, then X cannot be hydrogen, alkyl, haloalkyl,alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxyl or alkyl, and R″is hydrogen, alkyl or haloalkyl;

or, when R₅ and R₆ are independently selected from hydrogen or alkyl orR₅ and R₆ together form a carbon-carbon bond, E is a substituted aryl orheteroaryl, and X is NR′R″ wherein R′ is hydrogen or hydroxyl and R″ isCOR₁₁, then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R₅, R₆, R₇ and R₈ are independently selected from hydrogen,alkyl and alkoxy, or R₅ and R₆ form a carbon-carbon bond, R₇ ishydrogen, R₈ is hydrogen, alkoxy or alkyl, E is phenyl substituted withat least two hydroxyl groups or at least two alkoxy groups, and Y and Y′together is double-bonded oxygen, then X cannot be substituted alkoxy orNR′R″, where R′ is selected from hydrogen, alkyl, alkoxy, alkenyl,alkynyl, hydroxyalkyl, polyhydroxyalkyl, dialkylaminoalkyl, aminoalkyl,arylalkyl, phenyl, indanyl, carbocycoalkyl wherein the carbocycle is3-membered, heterocyclyl, and heterocyclylalkyl, where the heterocycleof the heterocyclyl and the heterocyclylalkyl is selected frompyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, and N-morpholino, andwherein any of the cyclic structures of the R′ is unsubstituted orsubstituted with one or more of halo, haloalkyl, alkoxy, hydroxy, amino,alkylamino, dialkylamino, and sulfonamido; and R″ is selected fromhydrogen, alkyl, alkylamino, cyanoalkyl, haloalkyl, hydroxyalkyl,dialkylaminoalkyl, alkylcarbonylalkylcarbonyloxy, and pyridinyl;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃, and R₄ ishalogen, Y and Y′ together is double-bonded oxygen, and X is NR′R″,wherein R′ is furanylalkyl and R″ is selected from hydrogen and COR₁₁,wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl, then E cannot be 3,4,5-trimethoxyphenyl;

or, when R′ is halophenylalkyl and R″ is hydrogen, then E cannot behalophenyl;

or, when n=0 and Y and Y′ together is double-bonded oxygen, then Xcannot be alkoxy, aryloxy, arylalkyloxy, or NR′R″ wherein R″ is hydrogenand R′ is alkyl, aryl, or arylalkyl.

In an embodiment, when R and R₀ are hydrogen, n is 1, three of R₁, R₂,R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or two ofR₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆ togetherform a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y and Y′together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is asubstituted aryl, then E cannot be a substituted aryl. For example, whenR and R₀ are hydrogen, n is 1, three of R₁, R₂, R₃, and R₄ are hydrogensand one is halogen, alkyl, or alkoxy or two of R₁, R₂, R₃ and R₄ arehydrogens and two are alkoxy, R₅ and R₆ together form a carbon-carbonbond, R₇ is hydrogen, R₈ is alkyl, Y and Y′ together is oxygen, X isNR′R″ wherein R″ is hydrogen, R′ is an aryl substituted with any ofhalo, alkoxy, amino, alkylamino, dialkylamino and sulfonamido, then Ecannot be a substituted aryl wherein two substituents are identicallyselected from hydroxyl and alkoxy.

The invention additionally provides a compound of formula I:

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

R₁, R₂, R₃, and R₄ are independently selected from hydrogen, halogen,alkyl, haloalkyl, hydroxyl, carboxyl, alkoxy, formyloxy, hydroxyalkyl,aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino,mercapto, alkylmercapto, cyano, cyanoalkyl, nitro, azido, andsubstituted or unsubstituted groups selected from alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, alkylsulfinyloxy, alkylsulfonyloxy, carbamate,carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,aminocarbonyloxyalkyloxy, arylcarbonyloxy, arylalkylcarbonyloxy,aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy andsulfamido, or any two of R₁, R₂, R₃ and R₄ form an alkylenedioxy group;

R₅, R₆, R₇ and R₈ are independently selected from hydrogen, alkyl andalkoxy, or R₅ and R₆ form a carbon-carbon bond, R₇ is hydrogen, R₈ ishydrogen, alkoxy or alkyl,

E is phenyl substituted with at least two hydroxyl groups or at leasttwo alkoxy groups, and at least one substituted or unsubstituted groupselected from phosphonooxy, phosphonoalkyloxy, formyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy;

Y and Y′ together is double-bonded oxygen;

X is substituted alkoxy or NR′R″, where R′ is selected from hydrogen,alkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocyclylalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl;

or a pharmaceutically acceptable salt thereof.

The invention further provides a compound of formula (II):

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

Y is hydrogen, alkyl, or haloalkyl, and Y′ is hydrogen, alkyl,cycloalkyl, haloalkyl, amino, alkylamino, or alkoxy, or Y and Y′together is double-bonded oxygen or double-bonded sulfur, or Y and Y′together is a double-bonded nitrogen bonded to hydrogen, hydroxyl,alkyl, or haloalkyl;

R₁, R₂, R₃, R₄, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ are independently selectedfrom hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, hydroxyl,carboxyl, alkoxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo,amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto,alkylmercapto, cyano, cyanoalkyl, nitro, azido, and substituted orunsubstituted groups selected from alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy, heterocyclylalkylcarbonyloxy, phosphonooxy,phosphonoalkyloxy and sulfonamido, or any two of R₁, R₂, R₃, and R₄ orany two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group;

R₇ and R₈ are independently selected from hydrogen, alkyl, haloalkyl,and alkoxy;

X is selected from hydrogen, alkyl, haloalkyl, alkoxy, alkylmercapto,and hydroxyl with the proviso that X is not hydroxyl when Y and Y′together is oxygen, or X is NR′R″, where R′ is selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryloxy, cyanoalkyl, haloalkyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, alkylamino, arylalkyl,arylalkenyl, arylcycloalkyl, arylcycloalkenyl, aryl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one, two, or threedouble bonds, 5-membered carbocyclic rings containing no double bond, orone or two double bonds, 4-membered carbocyclic rings containing nodouble bond or one double bond and 3-membered carbocyclic ringscontaining no double bond, heterocyclyl, and heterocyclylalkyl, wherethe heterocycle of the heterocyclyl and heterocyclylalkyl is selectedfrom 7-membered heterocyclic rings, 6-membered heterocyclic rings, and5-membered heterocyclic rings, and the aryl of the aryl, arylalkyl,arylalkylenyl, arylcycloalkyl, or arylcycloalkenyl structure or thecarbocyclic or heterocyclic structure is optionally substituted with oneor more of halo, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy, and sulfonamido; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when n is 1 or 2, Y and Y′ are hydrogens or Y andY′ together is double-bonded oxygen, and at least one of R₁₂, R₁₃, R₁₄,R₁₅ and R₁₆ is not hydrogen, then X cannot be hydrogen, alkyl,haloalkyl, alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxyl oralkyl, and R″ is hydrogen, alkyl or haloalkyl;

or, when X is NR′R″ wherein R′ is phenylalkyl and R″ is hydrogen, thentwo of R₁₂ to R₁₆ cannot be identically selected from hydroxyl oralkoxy;

or, when X is NR′R″ wherein R′ is hydrogen or hydroxyl, and R″ is COR₁₁,then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃, and R₄ ishalogen, Y and Y′ together is double-bonded oxygen and X is NR′R″wherein R′ is furanylalkyl and R″ is selected from hydrogen and COR₁₁,wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl, then R₁₃, R₁₄, and R₁₅ cannot each be methoxy;

or, when R and R₀ together is double-bonded oxygen and n is 1, then theheterocycle of the heterocyclyl or heterocyclylalkyl is furanyl orpyrrolyl;

or, when R′ is halophenylalkyl and R″ is hydrogen, then none of R₁₂,R₁₃, R₁₄, R₁₅ or R₁₆ can be halogen;

or, when n=0 and Y and Y′ together is double bonded oxygen, then Xcannot be alkoxy, aryloxy, arylalkyloxy, or NR′R″ wherein R″ is hydrogenand R′ is alkyl, aryl or arylalkyl.

In an embodiment, when R and R₀ are hydrogen, n is 1, three of R₁, R₂,R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or two ofR₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆ togetherform a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y and Y′together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is asubstituted aryl, then each of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ must behydrogen. For example, when R and R₀ are hydrogen, n is 1, three of R₁,R₂, R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or twoof R₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆together form a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y andY′ together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is anaryl substituted with any of halo, alkoxy, amino, alkylamino,dialkylamino, and sulfonamido, then no two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆can be identically selected from hydroxyl and alkoxy;

or, when R₇ is hydrogen, R₈ is hydrogen, alkoxy, or alkyl, least two ofR₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxyl oralkoxy, and Y and Y′ together is double-bonded oxygen, then X cannot besubstituted alkoxy or NR′R″, where R′ is selected from hydrogen, alkyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocycoalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl. For example, when R₇ ishydrogen and R₈ is selected from hydrogen, alkyl and alkoxy, at leasttwo of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxylor alkyl, Y and Y′ together is oxygen and R″ is hydrogen, then R′ cannotbe phenylalkyl.

The invention also provides a compound of formula (II):

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

Y is hydrogen, alkyl, or haloalkyl, and Y′ is hydrogen, alkyl,haloalkyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, orhaloalkyl;

R₁, R₂, R₃, R₄, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selectedfrom hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, hydroxyl,carboxyl, alkoxy, formyloxy, hydroxyalkyl, aldehydo, amino, alkylamino,aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto,cyano, cyanoalkyl, nitro, azido, and substituted or unsubstituted groupsselected from alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy, andsulfonamido, or any two of R₁, R₂, R₃ and R₄ or any two of R₁₂, R₁₃,R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group;

R₇ and R₈ are independently selected from hydrogen, alkyl, haloalkyl,and alkoxy;

X is selected from hydrogen, alkyl, haloalkyl, alkoxy, alkylmercapto,and hydroxyl with the proviso that X is not hydroxyl when Y and Y′together is oxygen, or X is NR′R″, where R′ is selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryloxy, cyanoalkyl, haloalkyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, alkylamino, arylalkyl,arylalkenyl, arylcycloalkyl, arylcycloalkenyl, aryl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one, two or three doublebonds, 5-membered carbocyclic rings containing no double bond, or one ortwo double bonds, 4-membered carbocyclic rings containing no double bondor one double bond and 3-membered carbocyclic rings containing no doublebond, heterocyclyl, and heterocyclylalkyl, where the heterocycle of theheterocyclyl and heterocyclylalkyl is selected from 7-memberedheterocyclic rings, 6-membered heterocyclic rings, and 5-memberedheterocyclic rings, and the aryl of the aryl, arylalkyl, arylalkylenyl,arylcycloalkyl, or arylcycloalkenyl structure or the carbocyclic orheterocyclic structure is optionally substituted with one or more ofhalo, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, cyanoalkyl,haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁ wherein R₁₁is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy, and sulfonamido; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when n is 1 or 2, Y and Y′ are hydrogens or Y andY′ together is double-bonded oxygen, and at least one of R₁₂, R₁₃, R₁₄,R₁₅ and R₁₆ is not hydrogen, then X cannot be hydrogen, alkyl,haloalkyl, alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxyl oralkyl, and R″ is hydrogen, alkyl or haloalkyl;

or, when X is NR′R″ wherein R′ is phenylalkyl and R″ is hydrogen, thentwo of R₁₂ to R₁₆ cannot be identically selected from hydroxyl oralkoxy;

or, when X is NR′R″ wherein R′ is hydrogen or hydroxyl, and R″ is COR₁₁,then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃ and R₄ ishalogen, Y and Y′ together is double-bonded oxygen and X is NR′R″wherein R′ is furanylalkyl and R″ is selected from hydrogen and COR₁₁,wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto and aryl, then R₁₃, R₁₄ and R₁₅ cannot each be methoxy;

or, when R′ is halophenylalkyl and R″ is hydrogen, then none of R₁₂,R₁₃, R₁₄, R₁₅ or R₁₆ can be halogen;

or, when n=0 and Y and Y′ together is double-bonded oxygen, then Xcannot be alkoxy, aryloxy, arylalkyloxy, or NR′R″ wherein R″ is hydrogenand R′ is alkyl, aryl or arylalkyl;

or, when the heterocycle of the heterocyclyl and heterocyclylalkyl of R′is selected from 7-membered heterocyclic rings, 6-membered heterocyclicrings, and 5-membered heterocyclic rings, and Y and Y′ together isdouble-bonded oxygen, then R₇ and R₈ are independently selected fromhydrogen, alkyl, haloalkyl, and alkoxy;

or, when the heterocycle of the heterocyclyl and heterocyclylalkyl of R′is selected from azepanyl, oxazepanyl, thiazepanyl, azepinyl, oxepinyl,thiepanyl, homopiperazinyl, diazepinyl, thiazepinyl, oxanyl, thianyl,pyranyl, thiopyranyl, thiomorpholinyl, dioxanyl, dithianyl, diazinyl,oxazinyl, thiazinyl, dioxinyl, dithiinyl, trioxanyl, trithianyl,triazinyl, tetrazinyl, tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolyl, furanyl, thiophenyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, furazanyl, oxadiazolyl,thiadiazolyl, dithiazolyl, and tetrazolyl, then R₇ and R₈ areindependently selected from hydrogen, alkyl, haloalkyl and alkoxy.

In an embodiment, when R and R₀ are hydrogen, n is 1, three of R₁, R₂,R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or two ofR₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆ togetherform a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y and Y′together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is asubstituted aryl, then each of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ must behydrogen. For example, when R and R₀ are hydrogen, n is 1, three of R₁,R₂, R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or twoof R₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆together form a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y andY′ together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is anaryl substituted with any of halo, alkoxy, amino, alkylamino,dialkylamino and sulfonamido, then no two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆can be identically selected from hydroxyl and alkoxy;

or, when R₇ is hydrogen, R₈ is hydrogen, alkoxy or alkyl, least two ofR₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxyl oralkoxy, and Y and Y′ together is double-bonded oxygen, then X cannot besubstituted alkoxy or NR′R″, where R′ is selected from hydrogen, alkyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocycoalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl. For example, when R₇ ishydrogen and R₈ is selected from hydrogen, alkyl and alkoxy, at leasttwo of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxylor alkyl, Y and Y′ together is oxygen and R″ is hydrogen, then R′ cannotbe phenylalkyl.

The compounds of the invention are suitable for treating or preventingcancer.

The present invention further provides a pharmaceutical compositioncomprising a compound described above and a pharmaceutically acceptablecarrier.

The present invention further provides a method of therapeutically orprophylactically treating a human or nonhuman mammalian patient withcancer comprising administering to said patient an anticancer effectiveamount of at least one compound of formula I or II, a pharmaceuticallyacceptable salt or prodrug thereof, either alone or in combination withat least one therapeutic agent which is not a compound of the presentinvention, or a pharmaceutically acceptable salt or prodrug thereof, forexample, an anticancer drug or radiation.

In an embodiment, the present invention provides a method oftherapeutically or prophylactically treating a human or nonhumanmammalian patient with a disease or condition treatable by theinhibition of one or more neoplastic or cancerous process, which methodcomprises administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of at least one neoplastic orcancerous inhibitory compound of formula I or II, as described above, ora pharmaceutically acceptable salt or prodrug thereof, either alone orin combination with at least one therapeutic agent which is not acompound of formula I or II as described above, or a pharmaceuticallyacceptable salt or prodrug thereof, for example an anticancer drug orradiation.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 depicts the chemical structures of sulindac and certainderivatives thereof reportedly having anticancer activity.

FIG. 2 depicts the chemical structures of certain other sulindacderivatives reported to inhibit Ras.

FIG. 3 shows chemical structures of selective Ras-inhibitory compoundsidentified by synthetic lethal screening.

FIG. 4 depicts the results of a Ras Binding Domain (RBD) pulldown assaypaired with Western blot showing the relative levels of Ras activationin a panel of colorectal cancer cell lines.

FIG. 5A reveals a correlation between sensitivity of tumor cells tocompound 004 and Ras activation status of the cells as determined byWestern blot analysis.

FIG. 5B reveals a correlation between sensitivity of tumor cells tocompound 006 and Ras activation status of the cells as determined byWestern blot analysis.

FIG. 5C reveals a correlation between sensitivity of tumor cells tocompound 007 and Ras activation status of the cells as determined byWestern blot analysis.

FIG. 5D reveals a correlation between sensitivity of tumor cells tocompound 010 and Ras activation status of the cells as determined byWestern blot analysis.

FIG. 6A-6F show Ras-selective tumor cell growth-inhibiting activity ofexemplary Ras-inhibitory compounds 006 (FIG. 6A), 007 (FIG. 6B), 019(FIG. 6C), 029 (FIG. 6D), 002 (FIG. 6E), and 022 (FIG. 6F) against humanHCT-116 colon tumor cells expressing mutant Ras, compared to human HT-29colon tumor cells expressing wild-type Ras. FIG. 6G-6J show similareffects of compounds 202 and 203 on HCT-116 and A549 cells as comparedto HT-29 cells, as labeled in the Figures accordingly.

FIG. 7A-7C illustrate treatment of a mammalian patient with a compoundof the present invention. FIG. 7A shows the effect of compound 030 (100mg/kg) on body weight for the duration of the experiment; data pointsare means±SE, n=9 (vehicle), n=10 (treatment). FIG. 7B shows the resultsof the aforementioned experiment, with tumor grading at necropsy; gradeassignments are as follows: 0=no tumors on chest or lungs, 1=tumorspresent on chest cavity but not lung, 2=tumors on lung and chest cavity,3=pleural effusions in addition to tumors on lung and chest cavity. FIG.7C shows the effect of the treatment with 030 (100 mg/kg) on tumorgrowth in live mice over the duration of the experiment as measured byluminescence; data points are means±SE, n=5.

FIG. 8A demonstrates that the HT-29 cells transfected with activated Raswere hypersensitive to the test drug (007) relative to the respectivecontrol cells.

FIG. 8B demonstrates that the H322 cells transfected with activated Raswere hypersensitive to the test drug (007) relative to the respectivecontrol cells.

FIG. 9 illustrates that representative Ras-inhibitory compounds (006 and007) used in the methods of the present invention interact with highaffinity directly with activated Ras to disrupt Ras interactions withits normal binding partner, Raf.

FIG. 10 shows that administration of antitumor therapeutic orpreventative doses of representative compounds (006, 007, and 019) asused in the present invention produced no evidence of in vivo animaltoxicity as assessed by animal weight gains over time. Compound 011 is acomparative compound.

FIG. 11A-11H illustrate that efficacious therapeutic (FIG. 11A-11D) orpreventive (FIG. 11E-11H) antitumor treatments of a representativeRas-driven tumor (HCT-116 human colon tumor xenografts) in vivo withexemplary Ras-inhibitory compounds 006, 007, 011 and 019 (named in FIGS.11A and 11E as ADT-006, in FIGS. 11B and 11F as ADT-007, in FIGS. 11Cand 11G as ADT-011 and in FIGS. 11D and 11H as ADT-019, respectively)employed in the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with an embodiment, the invention provides a compound offormula I:

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

R₁, R₂, R₃, and R₄ are independently selected from hydrogen, halogen,alkyl, haloalkyl, hydroxyl, carboxyl, alkoxy, formyloxy,alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl,alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto, cyano,cyanoalkyl, nitro, azido, and substituted or unsubstituted groupsselected from alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy andsulfonamido, or any two of R₁, R₂, R₃, and R₄ form an alkylenedioxygroup;

R₅, R₆, R₇, and R₈ are independently selected from hydrogen, alkyl,haloalkyl, and alkoxy; or R₅ and R₆ together form a carbon-carbon bond;

Y is hydrogen, alkyl, or haloalkyl, and Y′ is hydrogen, alkyl,haloalkyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, orhaloalkyl;

X is selected from hydrogen, alkyl, haloalkyl, alkoxy, alkylmercapto,and hydroxyl with the proviso that X is not hydroxyl when Y and Y′together is oxygen in a compound of formula I wherein R₅ and R₆ togetheris a carbon-carbon bond, or X is NR′R″, where R′ and R″ areindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryloxy, cyanoalkyl, haloalkyl, alkoxy, alkenyl, alkynyl,hydroxyalkyl, polyhydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminoalkyl, alkylamino, aryl, arylalkyl, arylalkenyl, arylcycloalkyl,arylcycloalkenyl, carbocyclyl, and carbocyclylalkyl where the carbocycleof the carbocyclyl and the carbocyclylalkyl is selected from 7-memberedcarbocyclic rings containing no double bond, or one, two or three doublebonds, 6-membered carbocyclic rings containing no double bond, or one,two or three double bonds, 5-membered carbocyclic rings containing nodouble bond, or one or two double bonds, 4-membered carbocyclic ringscontaining no double bond or one double bond and 3-membered carbocyclicrings containing no double bond, heterocyclyl, and heterocyclylalkyl,where the heterocycle of the heterocyclyl and heterocyclylalkyl isselected from 7-membered heterocyclic rings, 6-membered heterocyclicrings, and 5-membered heterocyclic rings, and the aryl of the aryl,arylalkyl, arylalkylenyl, arylcycloalkyl, or arylcycloalkenyl structureor the carbocyclic or heterocyclic structure is optionally substitutedwith one or more of halo, alkyl, haloalkyl, hydroxyl, alkoxy, amino,alkylamino, dialkylamino, mercapto, alkylmercapto, carboxamido,aldehydo, cyano, oxo, alkylcarbonyloxy, sulfonamido and COR₁₁, whereinR₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen and optionally oxygen or sulfur, and the heterocyclicring is optionally substituted with one or more of halo, alkyl,haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto,alkylmercapto, carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, andsulfonamido; and

E is a substituted or unsubstituted, saturated or unsaturated,7-membered, 6-membered, 5-membered, 4-membered or 3-membered carbocyclicor heterocyclic ring; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when E is a substituted aryl or heteroaryl, thenno substituent on the aryl or heteroaryl ring can be alkylsulfinyl oralkylsulfonyl, and no substituent on the aryl ring can be alkylmercapto,nor p-halo when R′ is dialkylaminoalkyl;

or, when R₅ and R₆ together is a carbon-carbon bond, R″ is hydrogen andR′ is a substituted arylalkyl, then E cannot be a substituted orunsubstituted heterocyclic ring selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, triazinyl, thiophenyl,furanyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, azinyl, tratrazolyl, pyridazinyl, and pyrrolyl;

or, when n is 1 or 2, R₅ and R₆ together form a carbon-carbon bond, Yand Y′ are hydrogens or Y and Y′ together is oxygen, and E is asubstituted phenyl, then X cannot be hydrogen, alkyl, haloalkyl,alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxyl or alkyl, and R″is hydrogen, alkyl or haloalkyl;

or, when R₅ and R₆ are independently selected from hydrogen or alkyl orR₅ and R₆ together form a carbon-carbon bond, E is a substituted aryl orheteroaryl, and X is NR′R″ wherein R′ is hydrogen or hydroxyl and R″ isCOR₁₁, then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R₅, R₆, R₇ and R₈ are independently selected from hydrogen,alkyl and alkoxy, or R₅ and R₆ form a carbon-carbon bond, R₇ ishydrogen, R₈ is hydrogen, alkoxy or alkyl, E is phenyl substituted withat least two hydroxyl groups or at least two alkoxy groups, and Y and Y′together is double-bonded oxygen, then X cannot be substituted alkoxy orNR′R″, where R′ is selected from hydrogen, alkyl, alkoxy, alkenyl,alkynyl, hydroxyalkyl, polyhydroxyalkyl, dialkylaminoalkyl, aminoalkyl,arylalkyl, phenyl, indanyl, carbocyclylalkyl wherein the carbocycle is3-membered, heterocyclyl, and heterocyclylalkyl, where the heterocycleof the heterocyclyl and the heterocyclylalkyl is selected frompyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, and N-morpholino, andwherein any of the cyclic structures of the R′ is unsubstituted orsubstituted with one or more of halo, haloalkyl, alkoxy, hydroxy, amino,alkylamino, dialkylamino, and sulfonamido; and R″ is selected fromhydrogen, alkyl, alkylamino, cyanoalkyl, haloalkyl, hydroxyalkyl,dialkylaminoalkyl, alkylcarbonylalkylcarbonyloxy, and pyridinyl;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃, and R₄ ishalogen, Y and Y′ together is double-bonded oxygen, and X is NR′R″,wherein R′ is furanylalkyl and R″ is selected from hydrogen and COR₁₁,wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl, then E cannot be 3,4,5-trimethoxyphenyl;

or, when R′ is halophenylalkyl and R″ is hydrogen, then E cannot behalophenyl;

or, when n=0 and Y and Y′ together is double-bonded oxygen, then Xcannot be alkoxy, aryloxy, arylalyloxy, or NR′R″ wherein R″ is hydrogenand R′ is alkyl, aryl or arylalkyl.

In an embodiment of formula I, R and R₀ are independently selected fromhydrogen, hydroxyl, alkyl, haloalkyl, amino, alkoxy and alkylamino, or Rand R₀ together is oxygen or sulfur, or R and R₀ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, orhaloalkyl; n is 0, 1 or 2;

R₁, R₂, R₃, and R₄ are independently selected from hydrogen, hydroxyl,halogen, alkyl, haloalkyl, alkoxy, and alkylmercapto;

R₅, R₆, R₇, R₈ are independently selected from hydrogen, alkyl,haloalkyl and alkoxy; or R₅ and R₆ together form a carbon-carbon bond;

Y is hydrogen, alkyl, or haloalkyl, and Y′ is hydrogen, alkyl,haloalkyl, amino, alkylamino, or alkoxy, or Y and Y′ together is oxygenor sulfur, or Y and Y′ together is a double-bonded nitrogen bonded tohydrogen, hydroxyl, alkyl, or haloalkyl;

X is selected from hydrogen, alkyl, haloalkyl, alkoxy, alkylmercapto,and hydroxyl with the proviso that X is not hydroxyl when Y and Y′together is oxygen in a compound of formula I wherein R₅ and R₆ togetheris a carbon-carbon bond, or X is NR′R″, where R′ is selected from thegroup consisting of hydrogen, hydroxyl, alkyl, haloalkyl, alkoxy,alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl, alkylaminoalkyl,dialkylaminoalkyl, aminoalkyl, alkylamino, aryl, arylalkyl, arylalkenyl,arylcycloalkyl, arylcycloalkenyl, carbocyclyl, and carbocyclylalkylwhere the carbocycle of the carbocyclyl and the carbocyclylalkyl isselected from 7-membered carbocyclic rings containing no double bond, orone, two or three double bonds, 6-membered carbocyclic rings containingno double bond, or one or two double bonds, 5-membered carbocyclic ringscontaining no double bond, or one or two double bonds, 4-memberedcarbocyclic rings containing no double bond or one double bond and3-membered carbocyclic rings containing no double bond, heterocyclyl,and heterocyclylalkyl, where the heterocycle of the heterocyclyl andheterocyclylalkyl is selected from 7-membered heterocyclic rings,6-membered heterocyclic rings, and 5-membered heterocyclic rings, andthe aryl of the aryl, arylalkyl, arylalkylenyl, arylcycloalkyl, orarylcycloalkenyl structure or the carbocyclic or heterocyclic structureis optionally substituted with one or more of halo, alkyl, haloalkyl,hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto,alkylmercapto, carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, andsulfonamido; and R″ is selected from hydrogen, alkyl, hydroxyalkyl,aminoalkyl, dialkylaminoalkyl, cyanoalkyl, haloalkyl,alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁ wherein R₁₁ isselected from hydrogen, amino, alkyl, haloalkyl, alkoxy, alkylmercapto,and aryl; or R′ and R″ together form a 5-, 6- or 7-membered, saturatedor unsaturated, heterocyclic ring containing at least one nitrogen, andoptionally oxygen and/or sulfur, and the heterocyclic ring is optionallysubstituted with one or more of halo, alkyl, haloalkyl, hydroxyl,alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto,carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido;and

E is a substituted or unsubstituted, saturated or unsaturated,7-membered, 6-membered, 5-membered, 4-membered or 3-membered carbocyclicor heterocyclic ring; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when E is a substituted aryl or heteroaryl, thenno substituent on the aryl or heteroaryl ring can be alkylsulfinyl oralkylsulfonyl, and no substituent on the aryl ring can be alkylmercapto,nor p-halo when R′ is dialkylaminoalkyl;

or, when R₅ and R₆ together is a carbon-carbon bond, R″ is hydrogen andR′ is a substituted arylalkyl, then E cannot be a substituted orunsubstituted heterocyclic ring selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, triazinyl, thiophenyl,furanyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, azinyl, tratrazolyl, pyridazinyl, and pyrrolyl;

or, when n is 1 or 2, R₅ and R₆ together form a carbon-carbon bond, Yand Y′ are hydrogens or Y and Y′ together is double-bonded oxygen, and Eis a substituted phenyl, then X cannot be hydrogen, alkyl, haloalkyl,alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxyl or alkyl, and R″is hydrogen, alkyl or haloalkyl;

or, when R₅ and R₆ are independently selected from hydrogen or alkyl orR₅ and R₆ together form a carbon-carbon bond, E is a substituted aryl orheteroaryl, and X is NR′R″ wherein R′ is hydrogen or hydroxyl and R″ isCOR₁₁, then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R₅, R₆, R₇ and R₈ are independently selected from hydrogen,alkyl and alkoxy, or R₅ and R₆ form a carbon-carbon bond, R₇ ishydrogen, R₈ is hydrogen, alkoxy or alkyl, E is phenyl substituted withat least two hydroxyl groups or at least two alkoxy groups, and Y and Y′together is double-bonded oxygen, then X cannot be substituted alkoxy orNR′R″, where R′ is selected from hydrogen, alkyl, alkoxy, alkenyl,alkynyl, hydroxyalkyl, polyhydroxyalkyl, dialkylaminoalkyl, aminoalkyl,arylalkyl, phenyl, indanyl, carbocyclylalkyl wherein the carbocycle is3-membered, heterocyclyl, and heterocyclylalkyl, where the heterocycleof the heterocyclyl and the heterocyclylalkyl is selected frompyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, and N-morpholino, andwherein any of the cyclic structures of the R′ is unsubstituted orsubstituted with one or more of halo, haloalkyl, alkoxy, hydroxy, amino,alkylamino, dialkylamino, and sulfonamido; and R″ is selected fromhydrogen, alkyl, alkylamino, cyanoalkyl, haloalkyl, hydroxyalkyl,dialkylaminoalkyl, alkylcarbonylalkylcarbonyloxy, and pyridinyl;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃, and R₄ ishalogen, Y and Y′ together is double-bonded oxygen, and X is NR′R″,wherein R′ is furanylalkyl and R″ is selected from hydrogen and COR₁₁,wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl, then E cannot be 3,4,5-trimethoxyphenyl;

or, when R′ is halophenylalkyl and R″ is hydrogen, then E cannot behalophenyl;

or, when n=0 and Y and Y′ together is double-bonded oxygen, then Xcannot be alkoxy, aryloxy, arylalkyloxy, or NR′R″ wherein R″ is hydrogenand R′ is alkyl, aryl, or arylalkyl.

In an embodiment, in R′, the 7-membered heterocyclic ring is selectedfrom azepanyl, oxazepanyl, thiazepanyl, azepinyl, oxepinyl, thiepanyl,homopiperazinyl, diazepinyl and thiazepinyl, the 6-membered heterocyclicring is selected from piperidinyl, oxanyl, thianyl, pyridinyl, pyranyl,thiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl,dithianyl, diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,trioxanyl, trithianyl, triazinyl and tetrazinyl, and the 5-memberedheterocyclic ring is selected from pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolyl, furanyl, thiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl.

In an embodiment, when R and R₀ are hydrogen, n is 1, three of R₁, R₂,R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or two ofR₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆ togetherform a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y and Y′together is double-bonded oxygen, X is NR′R″ wherein R″ is hydrogen, andR′ is a substituted aryl, then each of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ mustbe hydrogen. For example, when R and R₀ are hydrogen, n is 1, three ofR₁, R₂, R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy ortwo of R₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆together form a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y andY′ together is double-bonded oxygen, X is NR′R″ wherein R″ is hydrogen,and R′ is an aryl substituted with any of halo, alkoxy, amino,alkylamino, dialkylamino and sulfonamido, then no two of R₁₂, R₁₃, R₁₄,R₁₅ and R₁₆ can be identically selected from hydroxyl and alkoxy.

In another embodiment, E is a carbocyclic or heterocyclic ring,optionally substituted with one or more substituents selected fromhydroxyl, carboxyl, halogen, alkyl, haloalkyl, cyano, cyanoalkyl, nitro,oxo, alkoxy, formyloxy, amino, alkylamino, dialkylamino, aminoalkyl,alkylaminoalkyl, hydroxyalkyl, aldehydo, mercapto, alkylmercapto, azido,and substituted or unsubstituted groups selected from alkylsulfonyl,alkylsulfinyl, alkylsulfinyloxy, alkylsulfonyloxy, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,sulfonamido, and alkylenedioxy spanning two substituent positions.

In yet another embodiment, E is selected from cycloheptanyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclohexanyl,cyclohexenyl, cyclohexadienyl, phenyl, cyclopentanyl, cyclopentenyl,cyclopentadienyl, cyclopropanyl, cyclobutanyl, azepanyl, oxazepanyl,thiazepanyl, azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyl,thiazepinyl, piperidinyl, oxanyl, thianyl, pyridinyl, pyranyl,thiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl,dithianyl, diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,trioxanyl, trithianyl, triazinyl, tetrazinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, furanyl, thiophenyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, and tetrazolyl, eachof which is substituted or unsubstituted.

For example, the compound of formula (I), prodrug, or salt have E as:

wherein R₁₂, R₁₄, R₁₆, R₁₇, R₁₈ and R₁₉ are independently selected fromhydrogen, hydroxyl, carboxyl, halogen, alkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, aminoalkyl, alkylamino, alkylaminoalkyl,hydroxyalkyl, aldehydo, mercapto, alkylmercapto, azido, cyano,cyanoalkyl, nitro, and substituted or unsubstituted groups selected fromalkylsulfonyl, alkylsulfinyl, alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy, heterocyclylalkylcarbonyloxy, phosphonooxy,phosphonoalkyloxy, and sulfonamido.

In another embodiment, a prodrug of a compound of formula I has theformula I wherein any one of R₁, R₂, R₃, R₄, R′, R″, or any substituenton E is of the formula Q-U— wherein U is selected from the groupconsisting of oxygen, sulfur, nitrogen, OCH₂, SCH₂ and NHCH₂; and Q isselected from the group consisting of hydrogen, alkyl, PEG-CO, HCO,acetyl, amino acid, substituted benzoic acid, and phosphoric acid; or,wherein Q-U— together is selected from phosphonooxy, phosphonoalkyloxy,formyloxy, alkyloxy, alkylcarbonyloxy, alkylcarbonyloxyalkyloxy,aminocarbonyloxyalkyloxy, alkylsulfinyloxy, alkylsulfonyloxy, carbamate,carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy and heterocyclylalkylcarbonyloxy.

In a further embodiment, the invention provides a compound of formula I:

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

R₁, R₂, R₃, and R₄ are independently selected from hydrogen, halogen,alkyl, haloalkyl, hydroxyl, carboxyl, alkoxy, formyloxy, hydroxyalkyl,aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino,mercapto, alkylmercapto, cyano, cyanoalkyl, nitro, azido, andsubstituted or unsubstituted groups selected from alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, alkylsulfinyloxy, alkylsulfonyloxy, carbamate,carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,aminocarbonyloxyalkyloxy, arylcarbonyloxy, arylalkylcarbonyloxy,aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy andsulfamido, or any two of R₁, R₂, R₃ and R₄ form an alkylenedioxy group;

R₅, R₆, R₇ and R₈ are independently selected from hydrogen, alkyl andalkoxy, or R₅ and R₆ form a carbon-carbon bond, R₇ is hydrogen, R₈ ishydrogen, alkoxy or alkyl,

E is phenyl substituted with at least two hydroxyl groups or at leasttwo alkoxy groups, and at least one substituted or unsubstituted groupselected from phosphonooxy, phosphonoalkyloxy, formyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy;

Y and Y′ together is double-bonded oxygen;

X is substituted alkoxy or NR′R″, where R′ is selected from hydrogen,alkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocycoalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl;

or, a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of formula I, the inventionprovides a compound of formula I wherein R and R₀ are independentlyselected from hydrogen, hydroxyl, alkyl, alkoxy, alkylamino and amino;

at least one of R₁, R₂, R₃ and R₄ is hydrogen and three of R₁, R₂, R₃and R₄ are independently selected from hydrogen, hydroxyl, halogen,alkoxy, alkyl and alkylmercapto; n is 0, 1 or 2;

R₅ and R₆ together form a carbon-carbon bond, R₇ is hydrogen and R₈ isselected from hydrogen, alkyl and alkoxy;

E is phenyl substituted with at least two hydroxyl groups or at leasttwo alkoxy groups, and at least one substituted or unsubstituted groupselected from phosphonooxy, phosphonoalkyloxy, formyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy;

Y and Y′ together is double-bonded oxygen;

X is substituted alkoxy or NR′R″, where R′ is selected from hydrogen,alkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocycoalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl;

or, a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound of formula I,wherein R and R₀ are independently selected from hydrogen, hydroxyl,alkyl, alkoxy, alkylamino and amino;

at least one of R₁, R₂, R₃ and R₄ is hydrogen and three of R₁, R₂, R₃and R₄ are independently selected from hydrogen, hydroxyl, halogen,alkoxy, alkyl and alkylmercapto; n is 0, 1 or 2;

R₅ and R₆ together form a carbon-carbon bond, R₇ is hydrogen and R₈ isselected from hydrogen, alkyl and alkoxy;

E is phenyl substituted with at least two hydroxyl groups or at leasttwo alkoxy groups, and at least one substituted or unsubstituted groupselected from phosphonooxy, phosphonoalkyloxy, formyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy;

Y and Y′ together is a double-bonded oxygen;

X is substituted alkoxy or NR′R″, where R′ is selected from hydrogen,alkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocycoalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl;

or a pharmaceutically acceptable salt thereof.

In a further embodiment, the invention provides a compound of formula(II):

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

Y is hydrogen, alkyl, or haloalkyl, and Y′ is hydrogen, alkyl,haloalkyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, orhaloalkyl;

R₁, R₂, R₃, R₄, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ are independently selectedfrom hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, hydroxyl,carboxyl, alkoxy, formyloxy, hydroxyalkyl, aldehydo, amino, alkylamino,aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto,cyano, cyanoalkyl, nitro, azido, and substituted or unsubstituted groupsselected from alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy andsulfonamido, or any two of R₁, R₂, R₃, and R₄ or any two of R₁₂, R₁₃,R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group;

R₇ and R₈ are independently selected from hydrogen, alkyl, haloalkyl,and alkoxy;

X is selected from hydrogen, alkyl, haloalkyl, alkoxy, alkylmercapto,and hydroxyl with the proviso that X is not hydroxyl when Y and Y′together is oxygen, or X is NR′R″, where R′ is selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryloxy, cyanoalkyl, haloalkyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, alkylamino, arylalkyl,arylalkenyl, arylcycloalkyl, arylcycloalkenyl, aryl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one, two, or threedouble bonds, 5-membered carbocyclic rings containing no double bond, orone or two double bonds, 4-membered carbocyclic rings containing nodouble bond or one double bond and 3-membered carbocyclic ringscontaining no double bond, heterocyclyl, and heterocyclylalkyl, wherethe heterocycle of the heterocyclyl and heterocyclylalkyl is selectedfrom 7-membered heterocyclic rings, 6-membered heterocyclic rings, and5-membered heterocyclic rings, and the aryl of the aryl, arylalkyl,arylalkylenyl, arylcycloalkyl, or arylcycloalkenyl structure or thecarbocyclic or heterocyclic structure is optionally substituted with oneor more of halo, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy, and sulfonamido; or

a pharmaceutically acceptable salt thereof or a prodrug thereof.

In a preferred embodiment of the above, when n is 1 or 2, Y and Y′ arehydrogens or Y and Y′ together is double-bonded oxygen, and at least oneof R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ is not hydrogen, then X cannot behydrogen, alkyl, haloalkyl, alkylmercapto or NR′R″ wherein R′ ishydrogen, hydroxyl or alkyl, and R″ is hydrogen, alkyl or haloalkyl;

or, when X is NR′R″ wherein R′ is phenylalkyl and R″ is hydrogen, thentwo of R₁₂ to R₁₆ cannot be identically selected from hydroxyl oralkoxy;

or, when X is NR′R″ wherein R′ is hydrogen or hydroxyl, and R″ is COR₁₁,then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃, and R₄ ishalogen, Y and Y′ together is double-bonded oxygen and X is NR′R″wherein R′ is furanylalkyl and R″ is selected from hydrogen and COR₁₁,wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl, then R₁₃, R₁₄, and R₁₅ cannot each be methoxy;

or, when R′ is halophenylalkyl and R″ is hydrogen, then none of R₁₂,R₁₃, R₁₄, R₁₅ or R₁₆ can be halogen;

or, when n=0 and Y and Y′ together is double bonded oxygen, then Xcannot be alkoxy, aryloxy, arylalkyloxy, or NR′R″ wherein R″ is hydrogenand R′ is alkyl, aryl, or arylalkyl;

or, when R and R₀ together is double-bonded oxygen and n is 1, then theheterocycle of the heterocyclyl or heterocyclylalkyl is furanyl orpyrrolyl.

In an embodiment, a prodrug of a compound of formula II is a compound offormula II wherein any one of R₁, R₂, R₃, R₄, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R′, or R″ is of the formula Q-U— wherein U is selected from the groupconsisting of oxygen, sulfur, nitrogen, OCH₂, SCH₂ and NHCH₂, and Q isselected from the group consisting of hydrogen, alkyl, PEG-CO, HCO,acetyl, amino acid, substituted benzoic acid and phosphoric acid; or,wherein Q-U together is selected from phosphonooxy, phosphonoalkyloxy,formyloxy, alkyloxy, alkylcarbonyloxy, alkylcarbonyloxyalkyloxy,aminocarbonyloxyalkyloxy, alkylsulfinyloxy, alkylsulfonyloxy, carbamate,carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy and heterocyclylalkylcarbonyloxy.

In an embodiment, when R and R₀ are hydrogen, n is 1, three of R₁, R₂,R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or two ofR₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆ togetherform a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y and Y′together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is asubstituted aryl, then each of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ must behydrogen. For example, when R and R₀ are hydrogen, n is 1, three of R₁,R₂, R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or twoof R₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆together form a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y andY′ together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is anaryl substituted with any of halo, alkoxy, amino, alkylamino,dialkylamino and sulfonamido, then no two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆can be identically selected from hydroxyl and alkoxy;

or, when R₇ is hydrogen, R₈ is hydrogen, alkoxy or alkyl, least two ofR₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxyl oralkoxy, and Y and Y′ together is double-bonded oxygen, then X cannot besubstituted alkoxy or NR′R″, where R′ is selected from hydrogen, alkyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocycoalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl. For example, when R₇ ishydrogen and R₈ is selected from hydrogen, alkyl and alkoxy, at leasttwo of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxylor alkyl, Y and Y′ together is oxygen and R″ is hydrogen, then R′ cannotbe phenylalkyl.

In another embodiment, the invention provides a compound of formula(II):

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl,alkenylalkyl, alkynyl, alkynylalkyl, cyano, cyanoalkyl, halogen, azido,alkoxy, haloalkyl and a substituted or unsubstituted group selected fromaminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aminosulfonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, amino, alkylamino, dialkylamino,aminocarbonylalkylamino, and carbocyclylamino, carbocyclylalkylamino,heterocyclylamino and heterocyclylalkylamino wherein the ring structuresare saturated or unsaturated; or R and R₀ together is double-bondedoxygen or double-bonded sulfur, or R and R₀ together is a double-bondednitrogen bonded to one of hydrogen, hydroxyl, alkyl, or haloalkyl, or Rand R₀ together is a double-bonded carbon bonded to two substituentsindependently selected from hydrogen, hydroxyl, alkyl and haloalkyl, orR₀ is nitrogen which is part of a substituted or unsubstituted,saturated or unsaturated, 3-, 4-, 5-, 6- or 7-membered heterocyclicring; or R and R₀ together is a substituted or unsubstituted, saturatedor unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring;

n is 0, 1 or 2;

Y is hydrogen, alkyl, or haloalkyl, and Y′ is hydrogen, alkyl,haloalkyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, orhaloalkyl;

R₁, R₂, R₃, R₄, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selectedfrom hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, hydroxyl,carboxyl, alkoxy, formyloxy, hydroxyalkyl, aldehydo, amino, alkylamino,aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto,cyano, cyanoalkyl, nitro, azido, and substituted or unsubstituted groupsselected from alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy andsulfonamido, or any two of R₁, R₂, R₃ and R₄ or any two of R₁₂, R₁₃,R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group;

R₇ and R₈ are independently selected from hydrogen, alkyl, haloalkyl,and alkoxy;

X is selected from hydrogen, alkyl, aryloxy, cyanoalkyl, haloalkyl,alkoxy, alkylmercapto, and hydroxyl with the proviso that X is nothydroxyl when Y and Y′ together is oxygen, or X is NR′R″, where R′ isselected from the group consisting of hydrogen, hydroxyl, alkyl,haloalkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, alkylamino, arylalkyl,arylalkenyl, arylcycloalkyl, arylcycloalkenyl, aryl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one, two or three doublebonds, 5-membered carbocyclic rings containing no double bond, or one ortwo double bonds, 4-membered carbocyclic rings containing no double bondor one double bond and 3-membered carbocyclic rings containing no doublebond, heterocyclyl, and heterocyclylalkyl, where the heterocycle of theheterocyclyl and heterocyclylalkyl is selected from 7-memberedheterocyclic rings, 6-membered heterocyclic rings, and 5-memberedheterocyclic rings, and the aryl of the aryl, arylalkyl, arylalkylenyl,arylcycloalkyl, or arylcycloalkenyl structure or the carbocyclic orheterocyclic structure is optionally substituted with one or more ofhalo, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, cyanoalkyl,haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁ wherein R₁₁is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy, and sulfonamido; or

a pharmaceutically acceptable salt thereof or a prodrug thereof.

In a preferred embodiment of the above, when n is 1 or 2, Y and Y′ arehydrogens or Y and Y′ together is double-bonded oxygen, and at least oneof R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ is not hydrogen, then X cannot behydrogen, alkyl, haloalkyl, alkylmercapto or NR′R″ wherein R′ ishydrogen, hydroxyl or alkyl, and R″ is hydrogen, alkyl or haloalkyl;

or, when X is NR′R″ wherein R′ is phenylalkyl and R″ is hydrogen, thentwo of R₁₂ to R₁₆ cannot be identically selected from hydroxyl oralkoxy;

or, when X is NR′R″ wherein R′ is hydrogen or hydroxyl, and R″ is COR₁₁,then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃ and R₄ ishalogen, Y and Y′ together is double-bonded oxygen and X is NR′R″wherein R′ is furanylalkyl and R″ is selected from hydrogen and COR₁₁,wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto and aryl, then R₁₃, R₁₄ and R₁₅ cannot each be methoxy;

or, when R′ is halophenylalkyl and R″ is hydrogen, then none of R₁₂,R₁₃, R₁₄, R₁₅ or R₁₆ can be halogen;

or, when n=0 and Y and Y′ together is double bonded oxygen, then Xcannot be alkoxy, aryloxy, arylalkyloxy, or NR′R″ wherein R″ is hydrogenand R′ is alkyl, aryl, or arylalkyl;

or, when the heterocycle of the heterocyclyl and heterocyclylalkyl of R′is selected from 7-membered heterocyclic rings, 6-membered heterocyclicrings, and 5-membered heterocyclic rings, and Y and Y′ together isoxygen, then R₇ and R₈ are independently selected from hydrogen, alkyl,haloalkyl and alkoxy;

or, with the proviso that when the heterocycle of the heterocyclyl andheterocyclylalkyl of R′ is selected from azepanyl, oxazepanyl,thiazepanyl, azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyl,thiazepinyl, oxanyl, thianyl, pyranyl, thiopyranyl, thiomorpholinyl,dioxanyl, dithianyl, diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,trioxanyl, trithianyl, triazinyl, tetrazinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolyl, furanyl, thiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl, and tetrazolyl, then R₇ and R₈are independently selected from hydrogen, alkyl, haloalkyl and alkoxy.

In an embodiment, when R and R₀ are hydrogen, n is 1, three of R₁, R₂,R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or two ofR₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆ togetherform a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y and Y′together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is asubstituted aryl, then each of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ must behydrogen. For example, when R and R₀ are hydrogen, n is 1, three of R₁,R₂, R₃, and R₄ are hydrogens and one is halogen, alkyl, or alkoxy or twoof R₁, R₂, R₃ and R₄ are hydrogens and two are alkoxy, R₅ and R₆together form a carbon-carbon bond, R₇ is hydrogen, R₈ is alkyl, Y andY′ together is oxygen, X is NR′R″ wherein R″ is hydrogen, and R′ is anaryl substituted with any of halo, alkoxy, amino, alkylamino,dialkylamino and sulfonamido, then no two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆can be identically selected from hydroxyl and alkoxy;

or, when R₇ is hydrogen, R₈ is hydrogen, alkoxy or alkyl, least two ofR₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxyl oralkoxy, and Y and Y′ together is double-bonded oxygen, then X cannot besubstituted alkoxy or NR′R″, where R′ is selected from hydrogen, alkyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,dialkylaminoalkyl, aminoalkyl, arylalkyl, phenyl, indanyl,carbocycoalkyl wherein the carbocycle is 3-membered, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl and theheterocyclylalkyl is selected from pyridinyl, piperidinyl, piperazinyl,pyrrolidinyl, and N-morpholino, and wherein any of the cyclic structuresof the R′ is unsubstituted or substituted with one or more of halo,haloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, andsulfonamido; and R″ is selected from hydrogen, alkyl, alkylamino,cyanoalkyl, haloalkyl, hydroxyalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridinyl. For example, when R₇ ishydrogen and R₈ is selected from hydrogen, alkyl and alkoxy, at leasttwo of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are identically selected from hydroxylor alkyl, Y and Y′ together is oxygen and R″ is hydrogen, then R′ cannotbe phenylalkyl.

In the above embodiment of formula (II), in particular, X is NR′R″ whereR′ is selected from selected from alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl selectedfrom the group consisting of phenylalkyl, indanyl, heterocyclyl, andheterocyclylalkyl, where the heterocycle is selected from furanyl,pyrrolyl, thiophenyl, and imidazolyl, and the cyclic structure ofheterocyclyl and heterocyclylalkyl is optionally substituted with one ormore of halo, alkyl, haloalkyl, hydroxy, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, and carboxamido; R″ is selectedfrom hydrogen, alkyl, haloalkyl, cyanoalkyl, and dialkylaminoalkyl, orR′ and R″ together form a 5, 6, or 7-member heterocyclic ring, saturatedor unsaturated, substituted or unsubstituted, that contains at least onenitrogen and optionally oxygen.

In the above embodiment, preferably X is NR′R″ where R′ is selected fromalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, heterocyclyl, andheterocyclylalkyl where the heterocycle is selected from furanyl,pyrrolyl, and thiophenyl, and the cyclic structure of heterocyclyl andheterocyclylalkyl is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxy, alkoxy, amino, alkylamino, and dialkylamino;R″ is selected from hydrogen, alkyl, haloalkyl or dialkylaminoalkyl, orR′ and R″ together form a 5, 6, or 7-member heterocyclic ring, saturatedor unsaturated, substituted or unsubstituted, that contains at least onenitrogen and optionally oxygen.

In the above embodiment, more preferably X is NR′R″ where R′ is selectedfrom dialkylaminoalkyl, arylalkyl, heterocyclyl, and heterocyclylalkylwhere the heterocycle is selected from furanyl and pyrrolyl, and thecyclic structure is optionally substituted with one or more of halo,alkyl, haloalkyl, alkoxy, alkylamino and dialkylamino; and R″ isselected from hydrogen, alkyl, haloalkyl or dialkylaminoalkyl.

In the above embodiment, it is further preferred that X is NR′R″ whereR′ is benzyl, or a heterocyclyl or heterocyclylalkyl selected from2-furfuryl, 2-pyrrolylmethyl, and (1-methyl-1H-pyrrol-2-yl)methyl; andR″ is hydrogen.

In the above embodiment, it is more preferred that X is NR′R″ where R′is heterocyclyl or heterocyclylalkyl selected from 2-furfuryl,(1H-pyrrol-2-yl)methyl, and (1-methyl-1H-pyrrol-2-yl)methyl; and R″ ishydrogen.

In any of the embodiments of the compounds of formula (II) above, R andR₀ are independently selected from hydrogen and hydroxyl, and R₁, R₂, R₃and R₄ are independently selected from halogen, alkoxy, alkyl andhaloalkyl; n is 1; R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selectedfrom hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, formyloxy,alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl,alkylaminoalkyl, dialkylamino, mercapto, azido, and substituted orunsubstituted groups selected from alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, and sulfonamido, or any two of R₁₂, R₁₃, R₁₄, R₁₅and R₁₆ form an alkylenedioxy group.

In any of the embodiments of the compounds of formula (II) above, R₁,R₂, R₃ and R₄ are independently selected from halogen, alkoxy, alkyl andhaloalkyl; three of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independentlyselected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxy,formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino,aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, azido, andsubstituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, and sulfonamido, and one of R₁₂,R₁₃, R₁₄, R₁₅ and R₁₆ is independently selected from hydroxyl,hydroxyalkyl, amino, alkylamino, dialkylamino, and mercapto.

In any of the embodiments of the compounds of formula (II) above, threeof R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selected from hydrogen,halogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, aminoalkyl,alkylaminoalkyl, dialkylamino, and mercapto, and one of R₁₂, R₁₃, R₁₄,R₁₅ and R₁₆ is independently selected from hydroxyl, hydroxyalkyl,aldehydo, amino and alkylamino, dialkylamino, and mercapto; and R₈ ismethyl.

In the embodiments of the compounds of formula (II) above, R₂ isselected from halogen, alkoxy and alkylmercapto, R₁ and R₃ are hydrogen;and three of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selected fromhydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylamino,alkylaminoalkyl, and dialkylamino, and one of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆is independently selected from hydroxyl, hydroxyalkyl, amino,alkylamino, dialkylamino, and mercapto.

In a particular embodiment of the above compound, R₂ is selected fromhalogen and alkoxy, and R₁ and R₃ are hydrogen.

In the above embodiment, preferably R₂ is selected from fluoro andmethoxy.

In the prodrug of any of embodiments of formula (II), any of R₁₂, R₁₃,R₁₄, R₁₅ and R₁₆ is selected from phosphonooxy, phosphonoalkyloxy,formyloxy, alkyloxy, alkylcarbonyloxy, alkylcarbonyloxyalkyloxy,aminocarbonyloxyalkyloxy, alkylsulfinyloxy, alkylsulfonyloxy, carbamate,carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy and heterocyclylalkylcarbonyloxy.

Examples of compounds of the invention include:

-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (001),-   (Z)-2-(5-fluoro-1-(4-formoxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (002),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (006),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (007),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5,6-dimethoxy-2-methyl-1H-inden-3-yl)acetamide    (008),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (012),-   (Z)-2-(1-(3-bromo-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (013),-   (Z)-2-(1-(3-chloro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (014),-   (Z)-2-(1-(3-fluoro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (016),-   (Z)-2-(5-fluoro-1-((7-hydroxybenzo[d][1,3]dioxol-5-yl)methylene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (017),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide    (018),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (019),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(3-hydroxy-4-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (020),-   (Z)-2-(5-fluoro-1-(4-(hydroxymethyl)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (021),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (022),-   (Z)—N-(2-(dimethylamino)ethyl)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)acetamide    (026),-   (Z)-2-(5-fluoro-1-(4-mesyloxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (029),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (030),-   (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (031),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide    (032),-   (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide    (033),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(5-methylpyridin-3-yl)acetamide    (063),-   (Z)-2-(1-(4-aminocarbonyl-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (065),-   (Z)-methyl    2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-((1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)benzoate    (066),-   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (067),-   (Z)-2-(1-(3,5-dimethoxy-4-ureidobenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((4-methylpyridin-3-yl)methyl)acetamide    (069),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-ethoxycarbonyl-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (095),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (096),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide    (097),-   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((6-methylpyridin-2-yl)methyl)acetamide    (098),-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (099),-   (Z)-2-(5-fluoro-1-(4-mercapto-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (100),-   (Z)-2-(1-((6-(dimethylamino)pyridin-3-yl)methylene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (130),-   (Z)-2-(1-((2-(dimethylamino)pyrimidin-5-yl)methylene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (131),-   (Z)—N-(2-(dimethylamino)ethyl)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)acetamide    (132),-   (Z)—N-(2-(dimethylamino)ethyl)-2-(5-methoxy-2-methyl-1-(pyridin-4-ylmethylene)-1H-inden-3-yl)acetamide    (133),-   (Z)—N-(2-(dimethylamino)ethyl)-2-(1-((2-(dimethylamino)pyrimidin-5-yl)methylene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (134),-   (Z)—N-(furan-2-ylmethyl)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-methylacetamide    (135),-   (Z)-2-(1-(4-(dimethylamino)benzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(2-(dimethylamino)ethyl)-N-methylacetamide    (138),-   (R,Z)-1-(3-(dimethylamino)pyrrolidin-1-yl)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)ethanone    hydrochloride (139),-   (S,Z)-1-(3-(dimethylamino)pyrrolidin-1-yl)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)ethanone    hydrochloride (141),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-1-(4-methylpiperazin-1-yl)ethanone    hydrochloride (143),-   (R,Z)-2-(2,5-dimethyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethanone    hydrochloride (144),-   (S,Z)-2-(5,6-dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    hydrochloride (145),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-phenoxyacetamide    (151),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)-N-(trifluoromethyl)acetamide    (152),-   (Z)-2-(5-cyano-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (154),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethyl)-1H-inden-3-yl)acetamide    (155),

or the corresponding Z- or E-isomer thereof, prodrug, or salt thereof.

-   Preferred examples of the compounds include:-   (Z)-2-(5-fluoro-1-(4-formoxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (002),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (006),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (007),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide    (018),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (019),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (022),-   (Z)-2-(5-fluoro-1-(4-mesyloxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (029), and-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (030),

or the corresponding Z- or E-isomer thereof, prodrug, or salt thereof.

The structural formulas of the above compounds are as follows:

Examples of additional compounds of the invention, wherein R or R₀ isnot hydrogen are as follows:

-   (Z)-2-(benzylamino)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (202),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)-2-((pyridin-4-ylmethyl)amino)acetamide    (203),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-2-(1H-imidazol-1-yl)acetamide    (401),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-2-((furan-2-ylmethyl)amino)acetamide    (404),-   (Z)-2-(cyclopropylamino)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (410),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)-2-(pyrrolidin-1-yl)acetamide    (412),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)-2-((pyridin-3-ylmethyl)amino)acetamide    (413),-   (Z)-2-(dimethylamino)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-phenylacetamide    (415),-   (Z)-2-azido-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-phenylacetamide    (416),-   (Z)-2-(ethylamino)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (420),-   (Z)-2-(((1H-imidazol-2-yl)methyl)amino)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide    (423),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-2-((1-methylpyrrolidin-3-yl)amino)-N-(pyridin-3-ylmethyl)acetamide    (425),-   (Z)—N-benzyl-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-2-((oxazol-2-ylmethyl)amino)acetamide    (426),-   (Z)—N-benzyl-2-(cyclopropylamino)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide    (427),-   (Z)—N-benzyl-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-2-((pyridin-3-ylmethyl)amino)acetamide    (428),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)-2-((1-methylpyrrolidin-3-yl)amino)acetamide    (430),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)-2-((oxazol-2-ylmethyl)amino)acetamide    (431),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-2-((1-methylpiperidin-4-yl)amino)-N-(pyridin-2-ylmethyl)acetamide    (433),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)-2-((pyridin-3-ylmethyl)amino)acetamide    (434), and-   (Z)-2-cyano-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (436),

or the corresponding Z- or E-isomer thereof, prodrug, or salt thereof.

The structural formulas of the above compounds are as follows:

Examples of the prodrugs of the invention include:

-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    benzoate (214);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (300);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    benzoate (301);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    nicotinate (302);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (303);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (304);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (1-methylpiperidin-4-yl)carbamate (305);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (306);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (307);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (308);-   (Z)-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyl    dihydrogen phosphate (309);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    nicotinate (311);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (312);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (313);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (314);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (1-methylpiperidin-4-yl)carbamate (315);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (316);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (317);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (318);-   (Z)-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyl    dihydrogen phosphate (319);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    benzoate (320);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    nicotinate (321);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (322);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (323);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (324);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (1-methylpiperidin-4-yl)carbamate (325);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (326);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (327);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (328);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyl    dihydrogen phosphate (329);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    benzoate (330);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    nicotinate (331);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (332);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (333);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (334);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (1-methylpiperidin-4-yl)carbamate (335);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (336);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (338);-   (Z)-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyl    dihydrogen phosphate (339);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    benzoate (340);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    nicotinate (341);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (342);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (343);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (344);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (1-methylpiperidin-4-yl)carbamate (345);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (346);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (347);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (348);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyl    dihydrogen phosphate (349);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-(phenylamino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (350);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-(phenylamino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (351);-   (Z)-4-((5-fluoro-3-(2-((3-methoxyphenyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (352);-   (Z)-4-((5-fluoro-3-(2-((3-methoxyphenyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (353);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (4-nitrophenyl) carbonate (354);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (355);

or the corresponding Z- or E-isomer thereof, or pharmaceuticallyacceptable salts thereof.

The structural formulas of the above prodrugs are as follows.

The present invention further provides a method of therapeutically orprophylactically treating a human or nonhuman mammalian patient with adisease or condition treatable by the inhibition of one or moreneoplastic or cancerous process, which method comprises administering toa patient in need thereof a therapeutically or prophylacticallyeffective amount of at least one neoplastic or cancerous inhibitorycompound of formula (I) or (II) or a compound selected from (001),(002), (006)-(008), (012)-(014), (016)-(022), (026), (029)-(033), (063),(065)-(067), (069), (095)-(100), (130)-(135), (138), (139), (141),(143), (144), (145), (151), (152), (154), (155), (214), (300)-(309),(311)-(336), (338)-(353), (355), (202), (203), (401), (404), (410),(412), (413), (415), (416), (420), (423), (425)-(428), (430), (431),(433), (434), and (436), or a pharmaceutically acceptable salt orprodrug thereof, either alone or in combination with at least onetherapeutic agent other than a compound of formula (I) or (II) or acompound selected from (001), (002), (006)-(008), (012)-(014),(016)-(022), (026), (029)-(033), (063), (065)-(067), (069), (095)-(100),(130)-(135), (138), (139), (141), (143), (144), (145), (151), (152),(154), (155) (214), (300)-(309), (311)-(336), (338)-(353), (355), (202),(203), (401), (404), (410), (412), (413), (415), (416), (420), (423),(425)-(428), (430), (431), (433), (434), and (436), or apharmaceutically acceptable salt or prodrug thereof, for example, ananticancer drug or radiation.

In an embodiment, the neoplastic or cancerous process is selected fromgrowth, proliferation, survival, metastasis, drug resistance andradiation resistance of a tumor cell.

The present invention provides compounds as described above,pharmaceutically acceptable salts or prodrugs thereof, or thepharmaceutical composition, for use in the treatment or prophylaxis of ahuman or nonhuman mammalian patient with cancer.

In an embodiment, the cancer is selected from pancreatic cancer, lungcancer, colorectal cancer, melanoma, ovarian cancer, renal cancer,prostate cancer, head and neck cancer, endocrine cancer, uterine cancer,breast cancer, sarcoma cancer, gastric cancer, hepatic cancer,esophageal cancer, central nervous system cancer, brain cancer, hepaticcancer, germline cancer, lymphoma, and leukemia, particularly pancreaticcancer, colorectal cancer, and lung cancer.

In an embodiment of the above treatment or use, the cancer isdrug-resistant or radiation-resistant.

In an embodiment, prodrugs of the compounds of formula (II) includethose wherein any of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ is selected fromphosphonooxy, phosphonoalkyloxy, formyloxy, alkyloxy, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, alkoxycarbonyl,alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy.

The present invention also includes the following aspects:

1. A compound of formula I:

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,trifluoromethyl, amino, alkoxy and alkylamino, or R and R₀ together isoxygen or sulfur, or R and R₀ together is a single-bonded or adouble-bonded nitrogen bonded to one or more of hydrogen, hydroxyl,alkyl, and trifluoromethyl; n is 0, 1 or 2;

R₁, R₂, R₃, and R₄ are independently selected from hydrogen, hydroxyl,halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto;

R₅, R₆, R₇, R₈ are independently selected from hydrogen, alkyl,trifluoromethyl and alkoxy; or R₅ and R₆ together form a carbon-carbonbond;

Y is hydrogen, alkyl, or trifluoromethyl, and Y′ is hydrogen, alkyl,trifluoromethyl, amino, alkylamino, or alkoxy, or Y and Y′ together isoxygen or sulfur, or Y and Y′ together is a single-bonded or adouble-bonded nitrogen bonded to one or more of hydrogen, hydroxyl,alkyl, and trifluoromethyl;

X is selected from hydrogen, alkyl, trifluoromethyl, alkoxy,alkylmercapto, and hydroxyl with the proviso that X is not hydroxyl whenY and Y′ together is oxygen in a compound of formula I wherein R₅ and R₆together is a carbon-carbon bond, or X is NR′R″, where R′ is selectedfrom the group consisting of hydrogen, hydroxyl, alkyl, trifluoromethyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, aryl, arylalkyl,arylalkenyl, arylcycloalkyl, arylcycloalkenyl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one or two double bonds,5-membered carbocyclic rings containing no double bond, or one or twodouble bonds, 4-membered carbocyclic rings containing no double bond orone double bond and 3-membered carbocyclic rings containing no doublebond, heterocyclyl, and heterocyclylalkyl, where the heterocycle of theheterocyclyl and heterocyclylalkyl is selected from 7-memberedheterocyclic rings, 6-membered heterocyclic rings, and 5-memberedheterocyclic rings, and the aryl of the aryl, arylalkyl, arylalkylenyl,arylcycloalkyl, or arylcycloalkenyl structure or the carbocyclic orheterocyclic structure is optionally substituted with one or more ofhalo, alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, alkyl, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, amino, alkyl, trifluoromethyl,alkoxy, alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and

E is a substituted or unsubstituted, saturated or unsaturated,7-membered, 6-membered, 5-membered, 4-membered or 3-membered carbocyclicor heterocyclic ring; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when E is a substituted aryl or heteroaryl, thenno substituent on the aryl or heteroaryl ring can be alkylsulfinyl oralkylsulfonyl, and no substituent on the aryl ring can be alkylmercapto,nor p-halo when R′ is dialkylaminoalkyl;

or, when R₅ and R₆ together is a carbon-carbon bond, R″ is hydrogen andR′ is a substituted arylalkyl, then E cannot be a substituted orunsubstituted heterocyclic ring selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, triazinyl, thiophenyl,furanyl, thiazolyl, pyrazolyl and pyrrolyl;

or, when n is 1 or 2, R₅ and R₆ together form a carbon-carbon bond, Yand Y′ are hydrogens or Y and Y′ together is oxygen, and E is asubstituted phenyl, then X cannot be hydrogen, alkyl, trifluoromethyl,alkylmercapto or NR′R″ wherein R′ is hydrogen hydroxyl or alkyl, and R″is hydrogen, alkyl or haloalkyl;

or, when R₅ and R₆ are independently selected from hydrogen or alkyl orR₅ and R₆ together form a carbon-carbon bond, E is a substituted aryl orheteroaryl, and X is NR′R″ wherein R′ is hydrogen or hydroxyl and R″ isCOR₁₁, then R₁₁ cannot be alkyl, alkoxy or amino;

or, when R₅, R₆, R₇ and R₈ are independently selected from hydrogen,alkyl and alkoxy, or R₅ and R₆ form a carbon-carbon bond, R₇ ishydrogen, R₈ is hydrogen, alkoxy or alkyl, E is phenyl substituted withat least two hydroxyl groups or at least two alkoxy groups, and Y and Y′together is oxygen, then X cannot be substituted alkoxy or NR′R″, whereR′ is selected from hydrogen, alkyl, alkoxy, alkenyl, alkynyl,hydroxyalkyl, polyhydroxyalkyl, dialkylaminoalkyl, aminoalkyl,arylalkyl, phenyl, indanyl, heterocyclyl, and heterocyclylalkyl, wherethe heterocycle of the heterocyclyl and the heterocyclylalkyl isselected from pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, andN-morpholino, and wherein any of the cyclic structures of the R′ isunsubstituted or substituted with one or more of halo, alkoxy, hydroxy,amino, alkylamino, dialkylamino, and sulfonamido; and R″ is selectedfrom hydrogen, alkyl, alkylamino, cyanoalkyl, haloalkyl,dialkylaminoalkyl, alkylcarbonylalkylcarbonyloxy, and pyridinyl.

2. The compound, salt, or prodrug of aspect 1, wherein in R′, the7-membered heterocyclic ring is selected from azepanyl, oxazepanyl,thiazepanyl, azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyland thiazepinyl, the 6-membered heterocyclic ring is selected frompiperidinyl, oxanyl, thianyl, pyridinyl, pyranyl, thiopyranyl,piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, trioxanyl,trithianyl, triazinyl and tetrazinyl, and the 5-membered heterocyclicring is selected from pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolyl, furanyl, thiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl.

3. The compound, salt, prodrug of aspect 1 or 2, wherein E is acarbocyclic or heterocyclic ring, optionally substituted with one ormore substituents selected from hydroxyl, halogen, alkyl, haloalkyl,cyano, cyanoalkyl, nitro, oxo, alkoxy, formyloxy, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, hydroxyalkyl, aldehydo,mercapto, and alkylmercapto, azido, and substituted or unsubstitutedgroups selected from alkylsulfonyl, alkylsulfinyl, alkylsulfinyloxy,alkylsulfonyloxy, alkylcarbonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, sulfonamido, andalkylenedioxy spanning two substituent positions.

4. The compound of any one of aspects 1-3, prodrug, or a salt thereof,wherein E is selected from cycloheptanyl, cycloheptenyl,cycloheptadienyl, cycloheptatrienyl, cyclohexanyl, cyclohexenyl,cyclohexadienyl, phenyl, cyclopentanyl, cyclopentenyl, cyclopentadienyl,cyclopropanyl, cyclobutanyl, azepanyl, oxazepanyl, thiazepanyl,azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyl, thiazepinyl,piperidinyl, oxanyl, thianyl, pyridinyl, pyranyl, thiopyranyl,piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, trioxanyl,trithianyl, triazinyl, tetrazinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolyl, furanyl, thiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl, and tetrazolyl, each of which issubstituted or unsubstituted.

5. The compound, prodrug, or salt of aspect 4, wherein E is:

wherein R₁₂, R₁₄, R₁₆, R₁₇, R₁₈ and R₁₉ are independently selected fromhydrogen, hydroxyl, halogen, alkyl, trifluoromethyl, alkoxy, amino,alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, hydroxyalkyl,aldehydo, mercapto, alkylmercapto, azido, and substituted orunsubstituted groups selected from alkylsulfonyl, alkylsulfinyl,alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, and sulfonamido.

6. A compound of the formula (II):

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,trifluoromethyl, amino, alkoxy and alkylamino, or R and R₀ together isoxygen or sulfur, or R and R₀ together is a single-bonded or adouble-bonded nitrogen bonded to one or more of hydrogen, hydroxyl,alkyl, and trifluoromethyl; n is 0, 1 or 2;

Y is hydrogen, alkyl, or trifluoromethyl, and Y′ is hydrogen, alkyl,trifluoromethyl, amino, alkylamino, or alkoxy, or Y and Y′ together isoxygen or sulfur, or Y and Y′ together is a single-bonded or adouble-bonded nitrogen bonded to one or more of hydrogen, hydroxyl,alkyl, and trifluoromethyl;

R₁, R₂, R₃ and R₄ are independently selected from hydrogen, hydroxyl,halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto;

R₇ and R₈ are independently selected from hydrogen, alkyl,trifluoromethyl and alkoxy;

R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selected from hydrogen,halogen, alkyl, trifluoromethyl, hydroxyl, alkoxy, formyloxy,alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl,alkylaminoalkyl, dialkylamino, mercapto, azido, and substituted orunsubstituted groups selected from alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,and sulfonamido, or any two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form analkylenedioxy group;

X is selected from hydrogen, alkyl, trifluoromethyl, alkoxy,alkylmercapto, and hydroxyl with the proviso that X is not hydroxyl whenY and Y′ together is oxygen, or X is NR′R″, where R′ is selected fromthe group consisting of hydrogen, hydroxyl, alkyl, trifluoromethyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, arylalkyl, arylalkenyl,arylcycloalkyl, arylcycloalkenyl, aryl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one or two double bonds,5-membered carbocyclic rings containing no double bond, or one or twodouble bonds, 4-membered carbocyclic rings containing no double bond orone double bond and 3-membered carbocyclic rings containing no doublebond, heterocyclyl, and heterocyclylalkyl, where the heterocycle of theheterocyclyl and heterocyclylalkyl is selected from 7-memberedheterocyclic rings, 6-membered heterocyclic rings, and 5-memberedheterocyclic rings, and the aryl of the aryl, arylalkyl, arylalkylenyl,arylcycloalkyl, or arylcycloalkenyl structure or the carbocyclic orheterocyclic structure is optionally substituted with one or more ofhalo, alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, alkyl, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, amino, alkyl, trifluoromethyl,alkoxy, alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when n is 1 or 2, Y and Y′ are hydrogens or Y andY′ together is oxygen, and at least one of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ isnot hydrogen, then X cannot be hydrogen, alkyl, trifluoromethyl,alkylmercapto or NR′R″ wherein R′ is hydrogen hydroxyl or alkyl, and R″is hydrogen, alkyl or haloalkyl;

or, when at least one of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ is not hydrogen, andX is NR′R″ wherein R′ is hydrogen or hydroxyl, and R″ is COR₁₁, then R₁₁cannot be alkyl, alkoxy or amino;

or when R and R₀ together is oxygen and n is 1, then the heterocycle ofthe heterocyclyl or heterocyclylalkyl is furanyl or pyrrolyl.

7. A compound of formula (II):

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,trifluoromethyl, amino, alkoxy and alkylamino, or R and R₀ together isoxygen or sulfur, or R and R₀ together is a single-bonded or adouble-bonded nitrogen bonded to one or more of hydrogen, hydroxyl,alkyl, and trifluoromethyl; n is 0, 1 or 2;

Y is hydrogen, alkyl, or trifluoromethyl, and Y′ is hydrogen, alkyl,trifluoromethyl, amino, alkylamino, or alkoxy, or Y and Y′ together isoxygen or sulfur, or Y and Y′ together is a single-bonded or adouble-bonded nitrogen bonded to one or more of hydrogen, hydroxyl,alkyl, and trifluoromethyl;

R₁, R₂, R₃ and R₄ are independently selected from hydrogen, hydroxyl,halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto;

R₇ and R₈ are independently selected from hydrogen, alkyl,trifluoromethyl and alkoxy;

R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selected from hydrogen,halogen, alkyl, trifluoromethyl, hydroxyl, alkoxy, formyloxy,alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl,alkylaminoalkyl, dialkylamino, mercapto, azido, and substituted orunsubstituted groups selected from alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,and sulfonamido, or any two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form analkylenedioxy group;

X is selected from hydrogen, alkyl, trifluoromethyl, alkoxy,alkylmercapto, and hydroxyl with the proviso that X is not hydroxyl whenY and Y′ together is oxygen, or X is NR′R″, where R′ is selected fromthe group consisting of hydrogen, hydroxyl, alkyl, trifluoromethyl,alkoxy, alkenyl, alkynyl, hydroxyalkyl, polyhydroxyalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, arylalkyl, arylalkenyl,arylcycloalkyl, arylcycloalkenyl, aryl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one or two double bonds,5-membered carbocyclic rings containing no double bond, or one or twodouble bonds, 4-membered carbocyclic rings containing no double bond orone double bond and 3-membered carbocyclic rings containing no doublebond, heterocyclyl, and heterocyclylalkyl, where the heterocycle of theheterocyclyl and heterocyclylalkyl is selected from 7-memberedheterocyclic rings, 6-membered heterocyclic rings, and 5-memberedheterocyclic rings, and the aryl of the aryl, arylalkyl, arylalkylenyl,arylcycloalkyl, or arylcycloalkenyl structure or the carbocyclic orheterocyclic structure is optionally substituted with one or more ofhalo, alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, alkyl, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, amino, alkyl, trifluoromethyl,alkoxy, alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when n is 1 or 2, Y and Y′ are hydrogens or Y andY′ together is oxygen, and at least one of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ isnot hydrogen, then X cannot be hydrogen, alkyl, trifluoromethyl,alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxyl or alkyl, and R″is hydrogen, alkyl or haloalkyl;

or, when at least one of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ is not hydrogen, andX is NR′R″ wherein R′ is hydrogen or hydroxyl, and R″ is COR₁₁, then R₁₁cannot be alkyl, alkoxy or amino;

or, when the heterocycle of the heterocyclyl and heterocyclylalkyl of R′is selected from 7-membered heterocyclic rings, 6-membered heterocyclicrings, and 5-membered heterocyclic rings, and Y and Y′ together isoxygen, then R₇ and R₈ are independently selected from trifluoromethyland alkoxy; and

with the proviso that when the heterocycle of the heterocyclyl andheterocyclylalkyl of R′ is selected from azepanyl, oxazepanyl,thiazepanyl, azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyl,thiazepinyl, oxanyl, thianyl, pyranyl, thiopyranyl, thiomorpholinyl,dioxanyl, dithianyl, diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,trioxanyl, trithianyl, triazinyl, tetrazinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolyl, furanyl, thiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl, and tetrazolyl, then R₇ and R₈are independently selected from hydrogen, alkyl, trifluoromethyl andalkoxy.

8. The compound, prodrug, or salt of aspect 7, wherein X is NR′R″ whereR′ is selected from alkyl, trifluoromethyl, alkenyl, alkynyl,hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl selectedfrom the group consisting of benzyl, phenylalkyl, indanyl, heterocyclyl,and heterocyclylalkyl, where the heterocycle is selected from furanyl,pyrrolyl, thiophenyl, and imidazolyl, and the cyclic structure ofheterocyclyl and heterocyclylalkyl is optionally substituted with one ormore of halo, alkyl, trifluoromethyl, hydroxy, alkoxy, amino,alkylamino, dialkylamino, mercapto, alkylmercapto, and carboxamido; R″is selected from hydrogen, alkyl, cyanoalkyl, and dialkylaminoalkyl, orR′ and R″ together form a 5, 6, or 7-member heterocyclic ring, saturatedor unsaturated, substituted or unsubstituted, that contains at least onenitrogen and optionally oxygen.

9. The compound, prodrug, or salt of aspect 8, wherein X is NR′R″ whereR′ is selected from alkylaminoalkyl, dialkylaminoalkyl, arylalkyl,benzyl, heterocyclyl, and heterocyclylalkyl where the heterocycle isselected from furanyl, pyrrolyl, and thiophenyl, and the cyclicstructure of heterocyclyl and heterocyclylalkyl is optionallysubstituted with one or more of halo, alkyl, trifluoromethyl, hydroxy,alkoxy, amino, alkylamino, and dialkylamino; R″ is selected fromhydrogen, alkyl, and dialkylaminoalkyl, or R′ and R″ together form a 5,6, or 7-member heterocyclic ring, saturated or unsaturated, substitutedor unsubstituted, that contains at least one nitrogen and optionallyoxygen.

10. The compound, prodrug, or salt of aspect 9, wherein X is NR′R″ whereR′ is selected from dialkylaminoalkyl, arylalkyl, benzyl, heterocyclyl,and heterocyclylalkyl where the heterocycle is selected from furanyl andpyrrolyl, and the cyclic structure is optionally substituted with one ormore of halo, alkyl, trifluoromethyl, alkoxy, alkylamino anddialkylamino; and R″ is selected from hydrogen, alkyl, trifluoromethylor dialkylaminoalkyl.

11. The compound, prodrug, or salt of aspect 10, wherein X is NR′R″where R′ is benzyl, or a heterocyclyl or heterocyclylalkyl selected from2-furfuryl, 2-pyrrolylmethyl, and (1-methyl-1H-pyrrol-2-yl)methyl; andR″ is hydrogen.

12. The compound, prodrug, or salt of aspect 11, wherein X is NR′R″where R′ is heterocyclyl or heterocyclylalkyl selected 2-furfuryl,(1H-pyrrol-2-yl)methyl, and (1-methyl-1H-pyrrol-2-yl)methyl; and R″ ishydrogen.

13. The compound, prodrug, or salt of any one of aspects 6-12, wherein Rand R₀ are independently selected from hydrogen and hydroxyl, and R₁,R₂, R₃ and R₄ are independently selected from halogen, alkoxy, alkyl andtrifluoromethyl; n is 1; R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independentlyselected from hydrogen, halogen, alkyl, trifluoromethyl, hydroxyl,alkoxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, and sulfonamido, or any two ofR₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group.

14. The compound, prodrug, or salt of aspect 13, wherein R₁, R₂, R₃ andR₄ are independently selected from halogen, alkoxy, alkyl andtrifluoromethyl; three of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independentlyselected from hydrogen, halogen, alkyl, trifluoromethyl, hydroxyl,alkoxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, and sulfonamido, and one of R₁₂,R₁₃, R₁₄, R₁₅ and R₁₆ is independently selected from hydroxyl,hydroxyalkyl, amino, alkylamino, dialkylamino, and mercapto.

15. The compound, prodrug, or salt of aspect 14, wherein three of R₁₂,R₁₃, R₁₄, R₁₅ and R₁₆ are independently selected from halogen, alkyl,trifluoromethyl, alkoxy, amino, alkylamino, aminoalkyl, alkylaminoalkyl,dialkylamino, and mercapto, and one of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ isindependently selected from hydroxyl, hydroxyalkyl, aldehydo, amino,alkylamino, dialkylamino, and mercapto; and R₈ is methyl.

16. The compound, prodrug, or salt of aspect 6, wherein R₂ is selectedfrom halogen, alkoxy and alkylmercapto, R₁ and R₃ are hydrogen; andthree of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selected fromhydrogen, halogen, alkyl, trifluoromethyl, alkoxy, alkylamino,alkylaminoalkyl, and dialkylamino, and one of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆is independently selected from hydroxyl, hydroxyalkyl, amino,alkylamino, dialkylamino, and mercapto.

17. The compound, prodrug, or salt of aspect 16, wherein R₂ is selectedfrom halogen and alkoxy, and R₁ and R₃ are hydrogen.

18. The compound, prodrug, or salt of aspect 17, wherein R₂ is selectedfrom fluoro and methoxy.

19. A compound selected from:

-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (001),-   (Z)-2-(5-fluoro-1-(4-formoxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (002),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (006),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (007),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5,6-dimethoxy-2-methyl-1H-inden-3-yl)acetamide    (008),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (012),-   (Z)-2-(1-(3-bromo-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (013),-   (Z)-2-(1-(3-chloro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (014),-   (Z)-2-(1-(3-fluoro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (016),-   (Z)-2-(5-fluoro-1-((7-hydroxybenzo[d][1,3]dioxol-5-yl)methylene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (017),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide    (018),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (019),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(3-hydroxy-4-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (020),-   (Z)-2-(5-fluoro-1-(4-(hydroxymethyl)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (021),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (022),-   (Z)—N-(2-(dimethylamino)ethyl)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)acetamide    (026),-   (Z)-2-(5-fluoro-1-(4-mesyloxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (029),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (030),-   (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (031),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide    (032), and-   (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide    (033),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(5-methylpyridin-3-yl)acetamide    (063),-   (Z)-2-(1-(4-aminocarbonyl-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (065),-   (Z)-methyl    2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-((1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)benzoate    (066),-   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (067),-   (Z)-2-(1-(3,5-dimethoxy-4-ureidobenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((4-methylpyridin-3-yl)methyl)acetamide    (069),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-ethoxycarbonyl-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (095),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (096),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide    (097),-   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((6-methylpyridin-2-yl)methyl)acetamide    (098),-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (099),-   (Z)-2-(5-fluoro-1-(4-mercapto-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (100),

or the corresponding Z- or E-isomer thereof, prodrug, or salt thereof.

20. The compound, Z- or E-isomer prodrug, or salt of aspect 19, whereinthe compound is selected from:

-   (Z)-2-(5-fluoro-1-(4-formoxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (002),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (006),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (007),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide    (018),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (019),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (022),-   (Z)-2-(5-fluoro-1-(4-mesyloxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (029), and-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (030).

21. A pharmaceutical composition comprising a compound of any one ofaspects 1-20, a pharmaceutically acceptable salt or prodrug thereof, anda pharmaceutically acceptable carrier.

22. The pharmaceutical composition of aspect 21, further including atleast one additional therapeutic agent other than a compound of formulasI and II, a pharmaceutically acceptable salt or prodrug thereof.

23. A method of therapeutically or prophylactically treating a human ornonhuman mammalian patient with cancer comprising administering to saidpatient an anticancer effective amount of at least one compound of anyone of aspects 1-20, a pharmaceutically acceptable salt or prodrugthereof.

24. The method of aspect 23, wherein the cancer is selected frompancreatic cancer, lung cancer, colorectal cancer, melanoma, ovariancancer, renal cancer, prostate cancer, head and neck cancer, endocrinecancer, uterine cancer, breast cancer, sarcoma cancer, gastric cancer,hepatic cancer, esophageal cancer, central nervous system cancer, braincancer, hepatic cancer, germline cancer, lymphoma, and leukemia.

25. The method of aspect 24, wherein the cancer is selected frompancreatic cancer, colorectal cancer, and lung cancer.

26. The method of any one of aspects 23-25, wherein the cancer isdrug-resistant or radiation-resistant.

27. A method of therapeutically or prophylactically treating a human ornonhuman mammalian patient with a disease or condition treatable by theinhibition of one or more neoplastic or cancerous process, which methodcomprises administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of at least one neoplastic orcancerous inhibitory compound of any one of aspects 1-20 or a compoundselected from (001), (002), (006)-(008), (012)-(014), (016)-(022),(026), (029)-(033), (063), (065)-(067), (069), and (095)-(100) or apharmaceutically acceptable salt or prodrug thereof, either alone or incombination with one other therapeutic agent other than a compound ofany one of aspects 1-20 or a compound selected from (001), (002),(006)-(008), (012)-(014), (016)-(022), (026), (029)-(033), (063),(065)-(067), (069), and (095)-(100) or a pharmaceutically acceptablesalt or prodrug thereof.

28. The method of aspect 27, wherein the neoplastic or cancerous processis selected from growth, proliferation, survival, metastasis, drugresistance and radiation resistance of a tumor cell.

The present invention further provides the following preferred aspects:

1. A compound of formula I:

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,trifluoromethyl, amino, alkoxy and alkylamino, or R and R₀ together isdouble-bonded oxygen or double-bonded sulfur, or R and R₀ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, ortrifluoromethyl;

n is 1 or 2;

R₁, R₂, R₃, and R₄ are independently selected from hydrogen, hydroxyl,halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto;

R₅, R₆, R₇, R₈ are independently selected from hydrogen, alkyl,trifluoromethyl and alkoxy; or R₅ and R₆ together form a carbon-carbonbond;

Y is hydrogen, alkyl, or trifluoromethyl, and Y′ is hydrogen, alkyl,trifluoromethyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, ortrifluoromethyl;

X is selected from hydrogen, alkyl, trifluoromethyl, alkoxy,alkylmercapto, and hydroxyl with the proviso that X is not hydroxyl whenY and Y′ together is double-bonded oxygen in a compound of formula Iwherein R₅ and R₆ together is a carbon-carbon bond, or X is NR′R″, whereR′ is selected from the group consisting of hydrogen, hydroxyl, alkyl,trifluoromethyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl,polyhydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, aryl,arylalkenyl, arylcycloalkyl, arylcycloalkenyl, carbocyclyl, andcarbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one or two double bonds,5-membered carbocyclic rings containing no double bond, or one or twodouble bonds, 4-membered carbocyclic rings containing no double bond orone double bond, heterocyclyl, and heterocyclylalkyl, where theheterocycle of the heterocyclyl and heterocyclylalkyl is selected fromazepanyl, oxazepanyl, thiazepanyl, azepinyl, oxepinyl, thiepanyl,homopiperazinyl, diazepinyl, thiazepinyl, piperidinyl, oxanyl, thianyl,pyridinyl, pyranyl, thiopyranyl, piperazinyl, morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, diazinyl, oxazinyl, thiazinyl,dioxinyl, dithiinyl, trioxanyl, trithianyl, triazinyl, tetrazinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl,thiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl, andthe aryl of the aryl, arylalkylenyl, arylcycloalkyl, or arylcycloalkenylstructure or the carbocyclic or heterocyclic structure is optionallysubstituted with one or more of halo, alkyl, trifluoromethyl, hydroxyl,alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto,carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido;and R″ is selected from hydrogen, alkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, trifluoromethyl, alkylmercapto,and aryl; or R′ and R″ together form a 5-, 6- or 7-membered, saturatedor unsaturated, heterocyclic ring containing at least one nitrogen, andoptionally oxygen and/or sulfur, and the heterocyclic ring is optionallysubstituted with one or more of halo, alkyl, trifluoromethyl, hydroxyl,alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto,carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido;and

E is a substituted or unsubstituted phenyl or substituted orunsubstituted furanyl ring;

or a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that no substituent on the phenyl ring of E can bealkylsulfinyl or alkylsulfonyl, and no substituent on the phenyl ring ofE can be alkylmercapto, nor p-halo when R′ is dialkylaminoalkyl;

or, when R₅ and R₆ together form a carbon-carbon bond, Y and Y′ arehydrogens or Y and Y′ together is double-bonded oxygen, then X cannot behydrogen, alkyl, trifluoromethyl, alkylmercapto or NR′R″ wherein R′ ishydrogen, hydroxyl or alkyl, and R″ is hydrogen, alkyl or haloalkyl;

or, when R₅ and R₆ are independently selected from hydrogen or alkyl orR₅ and R₆ together form a carbon-carbon bond, E is a substituted orunsubstituted phenyl or substituted or unsubstituted furanyl, and X isNR′R″ wherein R′ is hydrogen or hydroxyl and R″ is COR₁₁, then R₁₁cannot be alkyl, alkoxy or amino;

or, when R₅, R₆, R₇ and R₈ are independently selected from hydrogen,alkyl and alkoxy, or R₅ and R₆ form a carbon-carbon bond, R₇ ishydrogen, R₈ is hydrogen, alkoxy or alkyl, E is phenyl substituted withat least two hydroxyl groups or at least two alkoxy groups, and Y and Y′together is double-bonded oxygen, then X cannot be alkoxy or NR′R″,where R′ is selected from hydrogen, alkyl, alkoxy, alkenyl, alkynyl,hydroxyalkyl, polyhydroxyalkyl, dialkylaminoalkyl, aminoalkyl, phenyl,indanyl, heterocyclyl, and heterocyclylalkyl, where the heterocycle ofthe heterocyclyl and the heterocyclylalkyl is selected from pyridinyl,piperidinyl, piperazinyl, pyrrolidinyl, and N-morpholino, and whereinany of the cyclic structures of the R′ is unsubstituted or substitutedwith one or more of halo, trifluoromethyl, alkoxy, hydroxy, amino,alkylamino, dialkylamino, and sulfonamido; and R″ is selected fromhydrogen, alkyl, cyanoalkyl, haloalkyl, dialkylaminoalkyl,alkylcarbonylalkylcarbonyloxy, and pyridyl;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃, and R₄ ishalogen, Y and Y′ together is double-bonded oxygen, and X is NR′R″,wherein R′ is furanylalkyl and R″ is selected from hydrogen, alkyl,hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, cyanoalkyl, haloalkyl,alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁ wherein R₁₁ isselected from hydrogen, amino, alkyl, trifluoromethyl, alkoxy,alkylmercapto, and aryl, then E cannot be 3,4,5-trimethoxyphenyl.

2. The compound, salt, prodrug of preferred aspect 1, wherein E is aphenyl ring, substituted with one or more substituents selected fromhydroxyl, halogen, alkyl, haloalkyl, cyano, cyanoalkyl, nitro, oxo,alkoxy, formyloxy, amino, alkylamino, dialkylamino, aminoalkyl,alkylaminoalkyl, hydroxyalkyl, aldehydo, mercapto, alkylmercapto, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, alkylcarbonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, sulfonamido, andalkylenedioxy spanning two substituent positions.

3. A compound of the formula (II):

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,trifluoromethyl, amino, alkoxy and alkylamino, or R and R₀ together isdouble-bonded oxygen or double-bonded sulfur, or R and R₀ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, ortrifluoromethyl;

n is 0, 1 or 2;

Y is hydrogen, alkyl, or trifluoromethyl, and Y′ is hydrogen, alkyl,trifluoromethyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, ortrifluoromethyl;

R₁, R₂, R₃ and R₄ are independently selected from hydrogen, hydroxyl,halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto;

R₇ and R₈ are independently selected from hydrogen, alkyl,trifluoromethyl and alkoxy;

R₁₄ is independently selected from hydrogen, halogen, alkyl,trifluoromethyl, hydroxyl, formyloxy, alkylcarbonyloxy, hydroxyalkyl,aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino,mercapto, azido, and substituted or unsubstituted groups selected fromalkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, and sulfonamido, orany two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group;

R₁₂, R₁₃, R₁₅ and R₁₆ are independently selected from hydrogen, halogen,alkyl, trifluoromethyl, hydroxyl, alkoxy, formyloxy, alkylcarbonyloxy,hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl,dialkylamino, mercapto, azido, and substituted or unsubstituted groupsselected from alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, and sulfonamido, orany two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group;

X is NR′R″, where R′ is furanyl or furanylalkyl wherein the furanyl ofthe furanyl or furanylalkyl is optionally substituted with one or moreof halo, alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, alkyl, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, trifluoromethyl, alkylmercapto,and aryl;

or a pharmaceutically acceptable salt thereof or a prodrug thereof

with the proviso that when n is 1 or 2, Y and Y′ are hydrogens or Y andY′ together is double-bonded oxygen, and at least one of R₁₂, R₁₃, R₁₄,R₁₅ and R₁₆ is not hydrogen, then X cannot be hydrogen, alkyl,trifluoromethyl, alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxylor alkyl, and X is NR′R″ wherein R′ is hydrogen, alkyl or haloalkyl;

or, when X is NR′R″ wherein R′ is hydrogen or hydroxyl, and R″ is COR₁₁,then R₁₁ cannot be alkyl, alkoxy or amino;

or, when X is NR′R″ wherein R′ is phenylalkyl and R″ is hydrogen, thentwo of R₁₂ to R₁₆ cannot be identically selected from hydroxyl oralkoxy;

or, when R and R₀ together is double-bonded oxygen and n is 1, then theheterocycle of the heterocyclyl or heterocyclylalkyl is furanyl orpyrrolyl;

or, when R and R₀ are hydrogens, at least one of R₁, R₂, R₃, and R₄ ishalogen, Y and Y′ together is double-bonded oxygen, and X is NR′R″wherein R′ is furanylalkyl and R″ is selected from hydrogen, alkyl,hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, cyanoalkyl, haloalkyl,alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁ wherein R₁₁ isselected from hydrogen, amino, alkyl, trifluoromethyl, alkoxy,alkylmercapto, and aryl, then R₁₃, R₁₄, and R₁₅ cannot each be methoxy.

4. The compound of preferred aspect 1, which is of the formula (II):

wherein:

R and R₀ are independently selected from hydrogen, hydroxyl, alkyl,trifluoromethyl, amino, alkoxy and alkylamino, or R and R₀ together isdouble-bonded oxygen or double-bonded sulfur, or R and R₀ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, ortrifluoromethyl;

n is 1 or 2;

Y is hydrogen, alkyl, or trifluoromethyl, and Y′ is hydrogen, alkyl,trifluoromethyl, amino, alkylamino, or alkoxy, or Y and Y′ together isdouble-bonded oxygen or double-bonded sulfur, or Y and Y′ together is adouble-bonded nitrogen bonded to hydrogen, hydroxyl, alkyl, ortrifluoromethyl;

R₁, R₂, R₃ and R₄ are independently selected from hydrogen, hydroxyl,halogen, alkyl, trifluoromethyl, alkoxy, and alkylmercapto;

R₇ and R₈ are independently selected from hydrogen, alkyl,trifluoromethyl and alkoxy;

R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independently selected from hydrogen,halogen, alkyl, trifluoromethyl, hydroxyl, alkoxy, formyloxy,alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl,alkylaminoalkyl, dialkylamino, mercapto, azido, and substituted orunsubstituted groups selected from alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,and sulfonamido, or any two of R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form analkylenedioxy group;

X is selected from hydrogen, alkyl, trifluoromethyl, alkoxy,alkylmercapto, and hydroxyl with the proviso that X is not hydroxyl whenY and Y′ together is double-bonded oxygen, or X is NR′R″, where R′ isselected from the group consisting of hydrogen, hydroxyl, alkyl,trifluoromethyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl,polyhydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl,arylalkenyl, arylcycloalkyl, arylcycloalkenyl, aryl, heterocyclyl, andheterocyclylalkyl, where the heterocycle of the heterocyclyl andheterocyclylalkyl is selected from azepanyl, oxazepanyl, thiazepanyl,azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyl, thiazepinyl,oxanyl, thianyl, pyranyl, thiopyranyl, thiomorpholinyl, dioxanyl,dithianyl, diazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,trioxanyl, trithianyl, triazinyl, tetrazinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolyl, thiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl, and tetrazolyl, and the aryl ofthe aryl, arylalkenyl, arylcycloalkyl, or arylcycloalkenyl or theheterocycle of the heterocyclyl or heterocyclylalkyl is optionallysubstituted with one or more of halo, alkyl, trifluoromethyl, hydroxyl,alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto,carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido;and R″ is selected from hydrogen, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, trifluoromethyl, alkylmercapto,and aryl; or R′ and R″ together form a 5-, 6- or 7-membered, saturatedor unsaturated, heterocyclic ring containing at least one nitrogen, andoptionally oxygen and/or sulfur, and the heterocyclic ring is optionallysubstituted with one or more of halo, alkyl, trifluoromethyl, hydroxyl,alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto,carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido; or

a pharmaceutically acceptable salt thereof or a prodrug thereof;

with the proviso that when Y and Y′ are hydrogens or Y and Y′ togetheris double-bonded oxygen, then X cannot be hydrogen, alkyl,trifluoromethyl, alkylmercapto or NR′R″ wherein R′ is hydrogen, hydroxylor alkyl, and R″ is hydrogen, alkyl or haloalkyl;

or, when the heterocycle of the heterocyclyl and heterocyclylalkyl of R′is selected from heterocyclyl and heterocyclylalkyl, and Y and Y′together is double-bonded oxygen, then R₇ and R₈ are independentlyselected from trifluoromethyl and alkoxy.

5. The compound, prodrug, or salt of preferred aspect 4, wherein X isNR′R″ where R′ is selected from alkyl, trifluoromethyl, alkenyl,alkynyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclyl,and heterocyclylalkyl, where the heterocycle is selected from pyrrolyl,thiophenyl, and imidazolyl, and the cyclic structure of heterocyclyl andheterocyclylalkyl is optionally substituted with one or more of halo,alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, and carboxamido; R″ is selectedfrom hydrogen, cyanoalkyl, and dialkylaminoalkyl, or R′ and R″ togetherform a 5-, 6- or 7-membered, saturated or unsaturated, heterocyclic ringcontaining at least one nitrogen, and optionally oxygen, and theheterocyclic ring is optionally be substituted with one or more of halo,alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido.

6. The compound, prodrug, or salt of preferred aspect 5, wherein X isNR′R″ where R′ is selected from alkylaminoalkyl, dialkylaminoalkyl,heterocyclyl, and heterocyclylalkyl where the heterocycle is selectedfrom pyrrolyl, and thiophenyl, and the cyclic structure of heterocyclyland heterocyclylalkyl is optionally substituted with one or more ofhalo, alkyl, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino, anddialkylamino; R″ is selected from hydrogen, and dialkylaminoalkyl, or R′and R″ together form a 5-, 6- or 7-membered, saturated or unsaturated,heterocyclic ring containing at least one nitrogen, and optionallyoxygen, and the heterocyclic ring is optionally be substituted with oneor more of halo, alkyl, trifluoromethyl, hydroxyl, alkoxy, amino,alkylamino, dialkylamino, mercapto, alkylmercapto, carboxamido,aldehydo, cyano, oxo, alkylcarbonyloxy, and sulfonamido.

7. The compound, prodrug, or salt of preferred aspect 6, wherein X isNR′R″ where R′ is selected from dialkylaminoalkyl, heterocyclyl, andheterocyclylalkyl where the heterocycle is pyrrolyl, which is optionallysubstituted with one or more of halo, alkyl, trifluoromethyl, alkoxy,alkylamino and dialkylamino; and R″ is hydrogen or dialkylaminoalkyl.

8. The compound, prodrug, or salt of preferred aspect 7, wherein X isNR′R″ where R′ is a heterocyclylalkyl selected from 2-pyrrolylmethyl and(1-methyl-1H-pyrrol-2-yl)methyl; and R″ is hydrogen.

9. The compound, prodrug, or salt of preferred aspect 8, wherein X isNR′R″ where R′ is a heterocyclylalkyl selected from(1H-pyrrol-2yl)methyl and (1-methyl-1H-pyrrol-2-yl)methyl; and R″ ishydrogen.

10. The compound, prodrug, or salt of preferred aspect 3, wherein R andR₀ are independently selected from hydrogen and hydroxyl, and R₁, R₂, R₃and R₄ are independently selected from hydrogen, halogen, alkoxy, alkyland trifluoromethyl; n is 1; R₁₂, R₁₃, R₁₅ and R₁₆ are independentlyselected from hydrogen, halogen, alkyl, trifluoromethyl, hydroxyl,alkoxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, and sulfonamido, or any two ofR₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group.

11. The compound, prodrug, or salt of preferred aspect 10, wherein R₁,R₂, R₃ and R₄ are independently selected from halogen, alkoxy, alkyl andtrifluoromethyl; three of R₁₂, R₁₃, R₁₅ and R₁₆ are independentlyselected from hydrogen, halogen, alkyl, trifluoromethyl, hydroxyl,alkoxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, and sulfonamido, and R₁₄ isselected from hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino,and mercapto.

12. The compound, prodrug, or salt of preferred aspect 11, wherein threeof R₁₂, R₁₃, R₁₅ and R₁₆ are independently selected from halogen, alkyl,trifluoromethyl, alkoxy, amino, alkylamino, aminoalkyl, alkylaminoalkyl,dialkylamino, and mercapto, and R₁₄ is selected from hydroxyl,hydroxyalkyl, aldehydo, amino, alkylamino, dialkylamino, and mercapto;and R₈ is methyl.

13. The compound, prodrug, or salt of preferred aspect 3, wherein R₂ isselected from halogen, alkoxy and alkylmercapto, R₁ and R₃ are hydrogen;and three of R₁₂, R₁₃, R₁₅ and R₁₆ are independently selected fromhydrogen, halogen, alkyl, trifluoromethyl, alkoxy, alkylamino,alkylaminoalkyl, and dialkylamino, and R₁₄ is selected from hydroxyl,hydroxyalkyl, amino, alkylamino, dialkylamino, and mercapto.

14. The compound, prodrug, or salt of preferred aspect 13, wherein R₂ isselected from halogen and alkoxy, and R₁ and R₃ are hydrogen.

15. The compound, prodrug, or salt of preferred aspect 14, wherein R₂ isselected from fluoro and methoxy.

16. The compound, the corresponding E-isomer, prodrug, or salt ofpreferred aspect 1, wherein the compound is selected from:

-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide    (018),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (019),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (022),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (030),-   (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (031),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide    (032),-   (Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide    (033),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(5-methylpyridin-3-yl)acetamide    (063),-   (Z)-2-(1-(4-aminocarbonyl-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (065),-   (Z)-methyl    2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-((1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)benzoate    (066),-   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide    (067),-   (Z)-2-(1-(3,5-dimethoxy-4-ureidobenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((4-methylpyridin-3-yl)methyl)acetamide    (069),-   (Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (096),-   (Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide    (097),-   (Z)-2-(1-(3,5-dimethoxy-4-sulfamoylbenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((6-methylpyridin-2-yl)methyl)acetamide    (098),-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    (2-(dimethylamino)ethyl)carbamate (099), and    (Z)-2-(5-fluoro-1-(4-mercapto-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (100).

17. A pharmaceutical composition comprising a compound of preferredaspect 1, a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier.

18. The pharmaceutical composition of preferred aspect 17, furtherincluding at least one therapeutic agent which is not a compound offormula I or II, a pharmaceutically acceptable salt or prodrug thereof.

19. A method of therapeutically or prophylactically treating a human ornonhuman mammalian patient with cancer comprising administering to saidpatient an anticancer effective amount of at least one compound ofpreferred aspect 1, a pharmaceutically acceptable salt or prodrugthereof.

20. The method of preferred aspect 19, wherein the cancer is selectedfrom pancreatic cancer, lung cancer, colorectal cancer, melanoma,ovarian cancer, renal cancer, prostate cancer, head and neck cancer,endocrine cancer, uterine cancer, breast cancer, sarcoma cancer, gastriccancer, hepatic cancer, esophageal cancer, central nervous systemcancer, brain cancer, hepatic cancer, germline cancer, lymphoma, andleukemia.

21. A method of therapeutically or prophylactically treating a human ornonhuman mammalian patient with a disease or condition treatable by theinhibition of one or more neoplastic or cancerous process, which methodcomprises administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of at least one neoplastic orcancerous inhibitory compound of preferred aspect 1, or a compoundselected from (001), (002), (006)-(008), (012)-(014), (016)-(022),(026), (029)-(033), (063), (065)-(067), (069), and (095)-(100) or apharmaceutically acceptable salt or prodrug thereof, either alone or incombination with one other therapeutic agent other than a compound ofpreferred aspect 1 or a compound selected from (001), (002),(006)-(008), (012)-(014), (016)-(022), (026), (029)-(033), (063),(065)-(067), (069), and (095)-(100) or a pharmaceutically acceptablesalt or prodrug thereof.

22. The compound, prodrug, or salt of preferred aspect 3, wherein R andR₀ are independently selected from hydrogen and hydroxyl, and R₁, R₂, R₃and R₄ are independently selected from halogen, alkoxy, alkyl andtrifluoromethyl; n is 1; R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are independentlyselected from hydrogen, halogen, alkyl, trifluoromethyl, hydroxyl,alkoxy, formyloxy, alkylcarbonyloxy, hydroxyalkyl, aldehydo, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, and sulfonamido, or any two ofR₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ form an alkylenedioxy group.

23. A pharmaceutical composition comprising a compound of preferredaspect 16, a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a compound of preferredaspect 3, a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier.

25. The pharmaceutical composition of preferred aspect 24, furtherincluding at least one therapeutic agent which is not a compound offormula I or II, a pharmaceutically acceptable salt or prodrug thereof,and a pharmaceutically acceptable carrier.

26. A method of therapeutically or prophylactically treating a human ornonhuman mammalian patient with cancer comprising administering to saidpatient an anticancer effective amount of at least one compound ofpreferred aspect 3, a pharmaceutically acceptable salt or prodrugthereof.

27. A method of therapeutically or prophylactically treating a human ornonhuman mammalian patient with a disease or condition treatable by theinhibition of one or more neoplastic or cancerous process, which methodcomprises administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of at least one neoplastic orcancerous inhibitory compound of preferred aspect 3 or apharmaceutically acceptable salt or prodrug thereof, either alone or incombination with at least one therapeutic agent which is not a compoundof formula I or II or a pharmaceutically acceptable salt or prodrugthereof.

28. A method of therapeutically or prophylactically treating a human ornonhuman mammalian patient with a disease or condition treatable by theinhibition of one or more neoplastic or cancerous process, which methodcomprises administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of at least one neoplastic orcancerous inhibitory compound of preferred aspect 1 or apharmaceutically acceptable salt or prodrug thereof, either alone or incombination with at least one therapeutic agent which is not a compoundof formula I or II, or a pharmaceutically acceptable salt or prodrugthereof.

29. The compound, the corresponding E-isomer, prodrug, or salt ofpreferred aspect 3, wherein the compound is selected from:

-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethylbenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (001),-   (Z)-2-(5-fluoro-1-(4-formoxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (002),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (006),-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (007),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-5,6-dimethoxy-2-methyl-1H-inden-3-yl)acetamide    (008),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-hydroxy-3-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (012),-   (Z)-2-(1-(3-bromo-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (013),-   (Z)-2-(1-(3-chloro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (014),-   (Z)-2-(1-(3-fluoro-4-hydroxy-5-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (016),-   (Z)-2-(5-fluoro-1-((7-hydroxybenzo[d][1,3]dioxol-5-yl)methylene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (017),-   (Z)—N-(furan-2-ylmethyl)-2-(1-(3-hydroxy-4-methoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (020),-   (Z)-2-(5-fluoro-1-(4-(hydroxymethyl)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (021),-   (Z)—N-(2-(dimethylamino)ethyl)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)acetamide    (026),-   (Z)-2-(5-fluoro-1-(4-mesyloxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (029), and-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-ethoxycarbonyl-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (095),

30. A pharmaceutical composition comprising the compound of preferredaspect 29, a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical compositioncomprising a compound as described above, a pharmaceutically acceptablesalt or prodrug thereof, and a pharmaceutically acceptable carrier.

In accordance with an embodiment, the pharmaceutical composition mayfurther include at least one therapeutic agent which is not a compoundof formula I or II, or salt or prodrug thereof.

In an embodiment, the present invention provides a method oftherapeutically or prophylactically treating a human or nonhumanmammalian patient with cancer, which method comprises administering to apatient in need thereof a therapeutically or prophylactically effectiveamount of at least one compound of formula I or II, either alone or incombination with at least one therapeutic agent which is not a compoundof formula I or II, or pharmaceutically acceptable salt or prodrugthereof, for example, an anticancer drug or radiation.

In an embodiment, the cancer is selected from pancreatic cancer, lungcancer, colorectal cancer, melanoma, ovarian cancer, renal cancer,prostate cancer, head and neck cancer, endocrine cancer, uterine cancer,breast cancer, sarcoma cancer, gastric cancer, hepatic cancer,esophageal cancer, central nervous system cancer, brain cancer, hepaticcancer, germline cancer, lymphoma, and leukemia, preferably pancreaticcancer, colorectal cancer, or lung cancer. In an embodiment, the canceris drug-resistant or radiation-resistant.

In a further embodiment, the invention provides a method oftherapeutically or prophylactically treating a human or nonhumanmammalian patient with a disease or condition treatable by theinhibition of one or more neoplastic or cancerous process, which methodcomprises administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of at least one neoplastic orcancerous inhibitory compound of formula I or II, or a compound selectedfrom (001), (002), (006)-(008), (012)-(014), (016)-(022), (026),(029)-(033), (063), (065)-(067), (069), (095)-(100), (130)-(135), (138),(139), (141), (143), (144), (145), (151), (152), (154), (155), (214),(300)-(309), (311)-(336), (338)-(353), (355), (202), (203), (401),(404), (410), (412), (413), (415), (416), (420), (423), (425)-(428),(430), (431), (433), (434), and (436), or a pharmaceutically acceptablesalt or prodrug thereof, either alone or in combination with at leastone therapeutic agent which is not a compound of formula I or II, orsalt or prodrug thereof, or a compound selected from (001), (002),(006)-(008), (012)-(014), (016)-(022), (026), (029)-(033), (063),(065)-(067), (069), (095)-(100), (130)-(135), (138), (139), (141),(143), (144), (145), (151), (152), (154), (155), (214), (300)-(309),(311)-(336), (338)-(353), (355), (202), (203), (401), (404), (410),(412), (413), (415), (416), (420), (423), (425)-(428), (430), (431),(433), (434), and (436), or a pharmaceutically acceptable salt orprodrug thereof, for example, an anticancer drug or radiation.

In a preferred embodiment of the above method, the neoplastic orcancerous process is selected from growth, proliferation, survival,metastasis, drug resistance and radiation resistance of a tumor cell.

In an embodiment, the compounds of the invention include Ras-inhibitorycompounds. A Ras-inhibitory compound can be identified from one or morecompounds of formulas I-II by an assay of Ras inhibition. Somerepresentative assays of selective Ras inhibition are illustrated in theexamples that follow herein. As used herein, the terminology selective“Ras inhibition” means selective, preferential or specific inhibition ofaberrant Ras-mediated cellular processes, such as, for example,accelerated or aberrant cell growth, proliferation, survival, andinvasiveness, relative to these processes in cells or tissues withnormal or non-aberrant Ras and Ras-mediated processes. Experimentally,selective Ras inhibition can be shown, for example, by determining theratio (numerator/denominator) of a given compound's potency (e.g., IC₅₀)to inhibit the growth of cells with “normal” or “wild-type” Ras(numerator) relative to that of cells with mutated and/or activated Ras(denominator). The terminology used herein for such an experimentallydetermined ratio is “selectivity” or “selectivity index”, which isfurther denoted by showing the respective cell types used to determinethe numerical ratio (e.g., HT-29/A549; Caco-2/SW-480; HT-29/SW-480;HT-29/CCT-116). For a given compound, a “selectivity” value or“selectivity index” of greater than 1 (one), preferably greater than 10(ten), more preferably greater than 100 (one hundred) and even morepreferably greater than 1000 (one thousand) indicates said compoundselectively inhibits hyperactive Ras and/or Ras-mediated cellularfunctions, such as those which may drive or accelerate cancer cellgrowth, proliferation, metastasis, resistance to drugs or radiation, andthe like.

In another preferred embodiment of the present invention, theaforementioned assay of Ras inhibition employs one or more isogenic cellline pair(s), wherein both of the lines share the same geneticbackground except that one of the lines (“mutant line”) contains one ormore mutated or hyperactive ras gene(s), Ras protein(s) and/or aberrantRas-mediated biological process(es), and the other line (“normal line”)lacks such mutation(s) or aberrant function(s).

In a further preferred embodiment of the present invention, theaforementioned assay employing isogenic cell line(s) enables thedetermination and calculation of a Ras-Inhibitory Specificity Index(RISI). One experimental approach to determination of such a RISI may,for example, comprise determining the ratio of the concentration of acompound producing a specified effect on the normal line, such as, forexample, 50% growth inhibition in a specified period of time, divided bythe concentration of the same compound producing the same specifiedeffect (e.g., 50% growth inhibition in the same specified period oftime) on the mutant line.

Whereas in the aforementioned approach, the 50% growth inhibition valuesmay be obtained by testing the compound against both normal and mutantcell lines at multiple concentrations over a specified concentrationrange, for example 10 nM-10,000 nM, an alternate, more streamlinedapproach to determining a RISI value could comprise measuring the ratioof percentage growth inhibition in a given period of time by a specifiedsingle concentration of the compound, for example 250 nM, selected fromwithin a range of concentrations, for example from within a range of 10nM-10,000 nM, against the mutant (numerator) relative to the normal cellline (denominator). This approach may be generally more applicable tolarger-scale or preliminary screening of groups of individual compoundsor mixtures thereof to obtain a preliminary or screening RISI, whereas aRISI determined using concentration ranges to determine 50% growthinhibition values may be more precise. A RISI value obtained for a givencompound by either approach may be less than, equal to or greater than 1(one), and a RISI value of greater than 1 (one) indicates said compoundselectively inhibits Ras or Ras-mediated cellular functions.

In a highly preferred embodiment of the present invention, the employedassay of Ras inhibition enables identification of a compound from one ormore compounds of formulas I-II having a RISI of greater than 1,preferably greater than 10, more preferably greater than 100, and evenmore preferably greater than 1000.

The present invention yet further provides a pharmaceutical compositioncomprising a therapeutically effective amount of Ras-inhibitory activityfrom one or more Ras-inhibitory compound(s) of formula I-II, orpharmaceutically acceptable salt(s) or prodrug(s) thereof, alone or incombination with at least one therapeutic agent which is not a compoundof formula I or II or salt or prodrug thereof. The therapeuticallyeffective amount can be that amount provided by a Ras-inhibiting and/ora disease-process inhibiting effective amount, such as an anticancereffective amount, of a compound of formula I or II or pharmaceuticallyacceptable salt or prodrug thereof.

In addition, the present invention provides a method of therapeuticallyor prophylactically treating a condition treatable by the inhibition ofRas-mediated biological processes including, for example, tumor cellgrowth, proliferation, survival, invasion and metastasis, as well asresistance to chemotherapy, other molecularly targeted therapeutics, andradiation; and, a method of therapeutically or prophylactically treatingcancers harboring hyperactive or mutant Ras. These methods compriseadministering a therapeutically or prophylactically effective amount ofRas-inhibiting activity from at least one Ras-inhibitory compound, orpharmaceutically acceptable salt or prodrug thereof, of formula I-II.

For example, the disease or condition treatable by the inhibition of oneor more Ras-mediated biological process is cancer, neurofibromatosis, orCostello syndrome. In an embodiment, the Ras-mediated biological processis selected from growth, proliferation, survival, metastasis, drugresistance and radiation resistance of a tumor cell.

In an embodiment of the above method, the patient is pre-selected byutilizing an assay of the patient's tissue, blood or tumor for anabnormal, mutant or hyperactive ras gene or Ras protein, or an aberrantRas-mediated biological process.

In an embodiment, the patient's tissue, blood or tumor contains anabnormal, mutant or hyperactive ras gene or Ras protein, or aberrantRas-mediated biological process.

The compounds in the present invention also can be in the form of apharmaceutically acceptable salt, which may include, for example, thesalt of one or more acidic substituents (e.g. a carboxylic salt, asulfonic acid salt, and the like) and the salt of one or more basicsubstituents (e.g. the salt of an amine, and the like). Suitable saltsof acidic substituents include, for example, metal salts (e.g. sodiumsalts, potassium salts, magnesium salts, zinc salts, and the like) andammonium salts (e.g., NH₄+ salts, alkylammonium salts, quaternaryammonium salts, and the like). Suitable salts of basic substituentsinclude, for example, acid addition salts (e.g., hydrochloride salts,hydrobromide salts, carboxylate salts (e.g., acetate salts), sulfatesalts, sulfonate salts (e.g., mesylate salts), phosphate salts,quaternary ammonium salts, and the like.

A compound of the present invention can also be provided as a prodrug,which is a drug derivative or drug precursor compound that typically isinactive or less than fully active until it is converted in the bodythrough a normal metabolic process such as, for example, hydrolysis ofan ester or amide form of the drug, to the active drug. A prodrug may beselected and used instead of the parent drug because, for example, inits prodrug form it is less toxic, and/or may have better absorption,distribution, metabolism and excretion (ADME) characteristics, and thelike, than the parent drug. A prodrug might also be used to improve howselectively the drug interacts with cells or processes that are not itsintended target. This approach may be employed particularly, forexample, to prevent or decrease adverse effects, especially in cancertreatments, which may be especially prone to having severe unintendedand undesirable side effects.

The term “prodrug” denotes a derivative of a compound, which derivative,when administered to warm-blooded animals, e.g. humans, is convertedinto the compound (drug). For example, the enzymatic and/or chemicalhydrolytic cleavage of a derivative compound of the present inventionoccurs in such a manner that the proven drug form is released, and themoiety or moieties split off remain nontoxic or are metabolized so thatnontoxic metabolites are produced. For example, a carboxylic acid groupcan be esterified, e.g., with a methyl group or ethyl group to yield anester. When an ester is administered to a subject, the ester is cleaved,enzymatically or non-enzymatically, reductively, oxidatively, orhydrolytically, to reveal the anionic group. An anionic group can beesterified with moieties (e.g., acyloxymethyl esters) which are cleavedto reveal an intermediate compound which subsequently decomposes toyield the active compound.

The prodrugs can be prepared in situ during the isolation andpurification of the compounds, or by separately reacting the purifiedcompound with a suitable derivatizing agent. For example, hydroxy groupscan be converted into esters via treatment with a carboxylic acid in thepresence of a catalyst. Examples of cleavable alcohol prodrug moietiesinclude substituted or unsubstituted, branched or unbranched alkyl estermoieties, e.g., ethyl esters, alkenyl esters, di-alkylamino alkylesters, e.g., dimethylaminoethyl ester, acylamino alkyl esters, acyloxyalkyl esters (e.g., pivaloyloxymethyl ester), aryl esters, e.g., phenylester, aryl-alkyl esters, e.g., benzyl ester, optionally substituted,e.g., with methyl, halo, or methoxy substituents aryl and aryl-alkylesters, amides, alkyl amides, di-alkyl amides, and hydroxy amides. Asanother example, an alkyloxy group can serve as a prodrug moiety for ahydroxyl group; for instance an alkoxy group on a phenyl ring can beenzymatically demethylated in vivo to yield a phenolic hydroxyl moiety.

Knowing the disclosures herein, it will be appreciated also that acompound of the present invention can be in the form of a prodrug, andthat such prodrugs can be prepared using reagents and synthetictransformations that are well-known to those having ordinary skill inthe art. The effectiveness of a particular prodrug can be determinedusing one or more analytical methods (e.g. pharmacokinetics, bioassays,in vivo efficacy studies, and the like) that are well-known to those ofordinary skill in the art.

More specifically, a prodrug having a formula of I or II may be preparedusing routine chemical procedures, such as the exemplary proceduresdescribed herein. For instance, any one of R₁, R₂, R₃, R₄, R′, R″ or anysubstituent on E of formula I can be of the formula Q-U—, for example,

wherein U is selected from the group consisting of oxygen, sulfur,nitrogen, OCH₂, SCH₂ and NHCH₂; and Q is selected from the groupconsisting of hydrogen, alkyl, PEG-CO, HCO, acetyl, amino acid,substituted benzoic acid and phosphoric acid; or, wherein Q-U— togetheris selected from phosphonooxy, phosphonoalkyloxy, formyloxy, alkyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy.

Similarly, in a compound of formula II any one of R₁, R₂, R₃, R₄, R₁₂,R₁₃, R₁₄, R₁₅, R₁₆, R′, or R″ can be of the formula Q-U— wherein U isselected from the group consisting of oxygen, sulfur, nitrogen, OCH₂,SCH₂ and NHCH₂; and Q is selected from the group consisting of hydrogen,alkyl, PEG-CO, HCO, acetyl, amino acid, substituted benzoic acid andphosphoric acid; or, wherein Q-U together is selected from phosphonooxy,phosphonoalkyloxy, formyloxy, alkyloxy, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, alkoxycarbonyl,alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy.

Suitable prodrugs may include, but not be limited to, those illustratedbelow for a compound of formula II, specifically as exemplary prodrugderivatives of compound 018:

wherein U is selected from the group consisting of oxygen, sulfur,nitrogen, OCH₂, SCH₂ and NHCH₂; and Q, for example, is selected from thegroup consisting of PEG-CO, HCO, acetyl, amino acid, substituted benzoicacid and phosphoric acid; or, Q-U together, for example, is substitutedor unsubstituted phosphonooxy, phosphonooxyalkyloxy, alkyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxy,aminocarbonyloxyalkyloxy, dimethylaminocarbonyloxy,dimethylaminocarbonyloxyalkyloxy, piperidinylcarbonyloxy,piperidinylcarbonyloxyalkyloxy, dipiperidinylcarbonyloxy, ordipiperidinylcarbonyloxyalkyloxy.

As used herein, the “alkyl” part of any of the substituents describedherein, e.g., but not limited to, alkyl, alkylamino, alkylmercapto,hydroxyalkyl, polyhydroxyalkyl, alkylaminoalkyl, aminoalkyl, arylalkyl,arylcycloalkyl, heterocyclylalkyl, arylalkylenyl, arylcycloalkyl,dialkylamino, alkylcarbonyloxy, dialkylaminoalkyl, cyanoalkyl,haloalkyl, alkylcarbonylalkylcarbonyloxy, dialkylalkylaminoalkyl,alkylsulfonyl, alkylsulfinyl, alkylsulfinyloxy, alkylsulfonyloxy,alkylenedioxy, carbocyclylalkyl, arylalkylcarbonyloxy,heteroarylcarbonyloxy, and phenylalkyl, means a straight-chain orbranched-chain saturated alkyl which can contain from 1-20 carbon atoms,for example from 1 to about 10 carbon atoms, or from 1 to about 8 carbonatoms, or, preferably, lower alkyl, i.e., from 1 to 6 carbon atoms.Unless otherwise specified herein, “alkyl” is assumed to mean loweralkyl.

Examples of alkyls include methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, octyl,dodecanyl, octadecyl, and the like. Alkyl substituents can beunsubstituted or substituted, for example with at least one substituentselected from the group consisting of a halogen, a nitro, an amino, ahydroxyl, a thio, an acyl, a mercapto, and a cyano.

The term “alkenyl” means a straight-chain or branched-chain alkenylhaving one or more double bonds. Unless otherwise specified, the alkenylcan contain from 2 to about 10 carbon atoms, for example from 2 to about8 carbon atoms, or preferably from 2 to about 6 carbon atoms. Examplesof alkenyls include vinyl, allyl, 1,4-butadienyl, and isopropenylsubstituents, and the like.

The term “alkynyl” means a straight-chain or branched-chain alkynylhaving one or more triple bonds. Unless otherwise specified, alkynylscan contain from 2 to about 10 carbon atoms, for example, from 2 toabout 8 carbon atoms, or preferably, from 2 to about 6 carbon atoms.Examples of alkynyls include ethynyl, propynyl (propargyl), butynyl, andthe like. Alkenyl or alkynyl substituents can be unsubstituted orsubstituted, for example, with at least one substituent selected fromthe group consisting of a halogen, a nitro, an amino, a hydroxyl, athio, an acyl, an alkyl, and a cyano.

The term “aryl” means an aromatic carbocyclic radical, as commonlyunderstood in the art, and includes monocyclic and polycyclic aromaticssuch as, for example, phenyl and naphthyl rings. Preferably, the arylcomprises one or more six-membered rings including, for example, phenyl,naphthyl, biphenyl, and the like. Typically, the aryl comprises six ormore carbon atoms in the ring skeleton thereof (e.g., from 6 to about 10carbon atoms making up the ring). Unless specified otherwise, “aryl” byitself refers to unsubstituted aryl groups and does not coversubstituted aryl groups. Substituted aryl can be an aryl substituted,for example, with at least one substituent selected from the groupconsisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl,and alkyl, and a cyano. It is to be noted that arylalkyl, benzyl, orheteroaryl groups are not considered “aryl” in accordance with thepresent invention.

In accordance with the invention, the term “heteroaryl” refers to acyclic aromatic radical having from five to ten ring atoms of which atleast one atom is O, S, or N, and the remaining atoms are carbon.Examples of heteroaryl radicals include pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,and isoquinolinyl. Unless otherwise specified, “heteroaryl” refers tounsubstituted heteroaryl.

In further accordance with the invention, the term “heterocyclyl” refersto a stable, saturated, partially unsaturated or unsaturated monocyclic,bicyclic, or spiro ring system containing 3 to 7 ring members of carbonatoms and other atoms selected from nitrogen, sulfur, and/or oxygen. Theterm “heterocyclyl” includes “heteroaryl groups. Preferably, aheterocyclyl is a 5, 6, or 7-membered monocyclic ring and contains one,two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur.The heterocyclyl may be attached alone or via an alkyl linker (thusbecoming a “heterocyclylalkyl”) to the parent structure through a carbonatom or through any heteroatom of the heterocyclyl that results in astable structure. Examples of such heterocyclyl rings are isoxazolyl,thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl,pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl.

Further in accordance with the invention, unless otherwise specified,the term “heterocyclyl” refers to a saturated or unsaturated,unsubstituted ring consisting of 3-7 atoms, at least one of which is nota carbon atom, such as an oxygen, nitrogen or sulfur atom.

Whenever a range of the number of atoms in a structure is indicated(e.g., a C₁₋₁₂, C₁₋₈, C₁₋₆, or C₁₋₄ alkyl, alkylamino, etc.), it isspecifically contemplated that any sub-range or individual number ofcarbon atoms falling within the indicated range also can be used. Thus,for instance, the recitation of a range of 1-8 carbon atoms (e.g.,C₁-C₈), 1-6 carbon atoms (e.g., C₁-C₆), 1-4 carbon atoms (e.g., C₁-C₄),1-3 carbon atoms (e.g., C₁-C₃), or 2-8 carbon atoms (e.g., C₂-C₈) asused with respect to any chemical group (e.g., alkyl, alkylamino, etc.)referenced herein encompasses and specifically describes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well asany sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms,1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms,2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms,2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbonatoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbonatoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms,and/or 4-12 carbon atoms, etc., as appropriate).

In light of the disclosures of the present invention, it will beappreciated that the compounds of the present invention can be made bymethods well-known to those of ordinary skill in the art, for example,by structurally modifying a given compound or by direct synthesis fromavailable building blocks using routine synthetic transformations thatare well-known in the art. See for example, Sperl et al., U.S. PatentApplication Publication No. US 2003/0009033 A1, Jan. 9, 2003; Sperl etal., U.S. Pat. No. 6,071,934, Jun. 6, 2000; Sperl et al., InternationalPublication No. WO 97/47303, Dec. 18, 1997; Whitehead et al., U.S.Patent Application Publication No. US 2003/0176316 A1, Sep. 18, 2003;Thompson et al., U.S. Pat. No. 6,538,029 B1, Mar. 25, 2003; Li et al.,U.S. Patent Application Publication No. US 2003/0194750 A1, Oct. 16,2003; and Shen et al., U.S. Pat. No. 3,888,902, Jun. 10, 1975; Alcalde,et al., Org. Biomol. Chem., 6, 3795-3810 (2008); Magar and Lee, Org.Lett., 15, 4288-4291 (2013).

For instance, a compound of formula I can be synthesized according tothe general approach depicted in Scheme I:

Detailed methods to achieve all of the synthesis steps depicted inScheme I to make a desired substituted or unsubstituted indenederivative, are extensively documented in the published literature(e.g., see Sperl, et. al., 1997, 2000, 2003, supra; Li, et. el., 2003,supra; Thompson, et. al., 2003, supra; Whitehead, et. al., 2003, supra);Alcatel, et al., 2008, supra; Magar and Lee, 2013, supra; Shen et al.,1975, supra. In Scheme I the benzaldehyde building block used for stepa, and/or the aldehyde building block (E-CHO) used for step f and/or theprimary or secondary amine (R′R″NH) building block used in step g canindependently be unsubstituted, or substituted with any desiredsubstituent(s) required to yield the desired final product of formula Ior II of the present invention.

For example, the benzaldehyde building block as shown in Scheme I havingthe desired substituents at R₁, R₂, R₃ and R₄ can be purchasedcommercially and/or can be prepared routinely by methods well-known tothose of ordinary skill in the art. Such optional substituent(s)independently at R₁, R₂, R₃ and R₄ in Scheme I for example include butare not limited to hydrogen, halogen, alkyl, cycloalkyl, haloalkyl,hydroxyl, carboxyl, alkoxy, formyloxy, hydroxyalkyl, aldehyde, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto,alkylmercapto, cyano, cyanoalkyl, nitro, azido, and substituted orunsubstituted groups selected from alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy, heterocyclylalkylcarbonyloxy, phosphonooxy,phosphonoalkyloxy, and sulfamido, or any two of R₁, R₂, R₃ and R₄ forman alkylenedioxy group.

Likewise, the aldehyde building block (E-CHO) as shown in Scheme Ihaving any desired group at E can be purchased and/or can be prepared bymethods well-known to those of ordinary skill in the art. Such optionalgroups at E in Scheme I for example include but are not limited to anydesired substituted or unsubstituted, saturated or unsaturated,7-membered, 6-membered, 5-membered, 4-membered or 3-membered carbocyclicor heterocyclic ring. Substituents on said ring may include one or moreof hydrogen, halogen, alkyl, haloalkyl, hydroxyl, carboxyl, alkoxy,formyloxy, hydroxyalkyl, aldehyde, amino, alkylamino, aminoalkyl,alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto, cyano,cyanoalkyl, nitro, azido, and substituted or unsubstituted groupsselected from alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy, andsulfonamido, or any two of R₁, R₂, R₃ and R₄ form an alkylenedioxygroup.

Furthermore, the primary or secondary amine building block (R′R″NH) asshown in Scheme I can be purchased commercially and/or can be preparedroutinely by methods well-known to those of ordinary skill in the art.Such optional substituents independently at R′ and R″ in Scheme I forexample include but are not limited to hydrogen, hydroxyl, alkyl,aryloxy, cyanoalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl,polyhydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, aryl,arylalkyl, arylalkenyl, arylcycloalkyl, arylcycloalkenyl, carbocyclyl,and carbocyclylalkyl where the carbocycle of the carbocyclyl and thecarbocyclylalkyl is selected from 7-membered carbocyclic ringscontaining no double bond, or one, two or three double bonds, 6-memberedcarbocyclic rings containing no double bond, or one or two double bonds,5-membered carbocyclic rings containing no double bond, or one or twodouble bonds, 4-membered carbocyclic rings containing no double bond orone double bond and 3-membered carbocyclic rings containing no doublebond, heterocyclyl, and heterocyclylalkyl, where the heterocycle of theheterocyclyl and heterocyclylalkyl is selected from 7-memberedheterocyclic rings, 6-membered heterocyclic rings, and 5-memberedheterocyclic rings, and the aryl of the aryl, arylalkyl, arylalkylenyl,arylcycloalkyl, or arylcycloalkenyl structure or the carbocyclic orheterocyclic structure is optionally substituted with one or more ofhalo, alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy, and sulfonamido; and R″ is selected fromhydrogen, alkyl, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl,cyanoalkyl, haloalkyl, alkylcarbonylalkylcarbonyloxy, pyridyl, and COR₁₁wherein R₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen, and optionally oxygen and/or sulfur, and theheterocyclic ring is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy, and sulfonamide.

As a more specific example, a particular compound of formula II can besynthesized according to the general approach depicted in Scheme II,which includes the key intermediate, a substituted indenyl acetic acid:

For certain substituents at R₁, R₂, R₃ or R₄ (e.g., in Scheme II above,R₂ is fluoro), the starting material for preparation of the substitutedindenyl acetic acid intermediate, is optionally different than thatshown in Schemes I and II, depending upon the nature of thesubstituent(s) desired on the intermediate and final product, and theoptimum reaction conditions sought. For example, attachment of a cyanogroup at R₂ can be accomplished using as starting material acyano-substituted benzyl halide (e.g., as adapted from Shen, et. al.,1975), as illustrated below in Scheme III:

A wide variety of substituents can be introduced at R₁, R₂, R₃ and R₄ ofa compound of formula I or II in the course of synthesis. In addition tothe above-described Schemes I-III, Scheme IV below illustrates yetanother approach to making variations in substituents at R₁-R₄.

Extensive variations can also be made in R and/or R₀ in a medicallyuseful compound of formula I or II of the invention. For example, oneskilled in the art can use or adapt as necessary the general synthesisapproach illustrated by Scheme V below.

In a more specific example illustrated in Scheme VI below, a compound ofthe invention, such as compound 007, can serve as the starting point formaking other medically useful derivatives thereof which have variousdifferent substituents at R and/or R₀, such as compounds 202, 203, 404,410, 430 and 431.

Furthermore, variations in the length of the side-chain linkers in thecompounds of formula I or II can be introduced by one of ordinary skillin the art by adapting known methods. For example, adaptations of themethods of Magar and Lee 2013, supra, can be used to produce compoundsof formula I and II wherein n=0.

Yet more specific and detailed illustrations using these generalsynthetic approaches are provided in the particular Examples that followherein. Furthermore, one skilled in the art and knowing the disclosuresof the present invention will appreciate that any of compounds offormula I or II can be modified with different substituents as desiredto be in the final products, and/or the final product of a synthesis,for example a synthesis according to Scheme I, II, III, IV, V, or VI canbe modified with different substituents as desired. Placement, removaland/or inter-conversion of desired substituents on precursors, buildingblocks, intermediates or penultimate product compounds of formulas I andII can be accomplished by routine methods well-known to those ofordinary skill in the art, as briefly overviewed in the following:

One or more hydroxyl groups, for example, can be converted to the oxoderivative by direct oxidation, which can be accomplished using anyknown method such as, for example, a Swern oxidation, or by reactionwith a metal oxidant, such as a chromium oxide (e.g., chromiumtrioxide), a manganese oxide (e.g., manganese dioxide or permanganate)or the like. Primary alcohols can be oxidized to aldehydes, for example,via Swern oxidation, or they can be oxidized to carboxylic acids (e.g.,—CO₂H), for example by reaction with a metal oxidant. Similarly, thethiols (e.g., —SR, —SH, and the like) can be converted to oxidizedsulfur derivatives (e.g., —SO₂R or the like) by reaction with anappropriate oxidant.

One or more hydroxyl groups can be converted to an ester (e.g., —CO₂R),for example, by reaction with an appropriate esterifying agent such asfor example, an anhydride (e.g., (R(CO))₂O) or an acid chloride (e.g.,R(CO)Cl), or the like. One or more hydroxyl groups can be converted to asulfonate (e.g., —SO₂R) by reaction with an appropriate sulfonatingagent such as, for example, a sulfonyl chloride (e.g., RSO₂Cl), or thelike, wherein R is any suitable substituent including, for example,organic substituents described herein. Ester derivatives also can beobtained, for example, by reacting one or more carboxylic acidsubstituents (e.g., —CO₂H) with an alkylating agent such as, forexample, a diazoalkane (e.g., diazomethane) an alkyl or aryl iodide, orthe like. One or more amides can be obtained by reaction of one or morecarboxylic acids with an amine under appropriate amide-formingconditions which include, for example, activation of a carboxylic acid(e.g., by conversion to an acid chloride or by reaction with acarbodiimide reagent) followed by coupling of the activated species witha suitable amine.

One or more hydroxyl groups can be converted to a halogen using ahalogenating agent such as, for example, an N-halosuccinamide such asN-iodosuccinamide, N-bromosuccinamide, N-chlorosuccinamide, or the like,in the presence of a suitable activating agent (e.g., a phosphine, orthe like). One or more hydroxyl groups also can be converted to ether byreacting one or more hydroxyls, for example, with an alkylating agent inthe presence of a suitable base. Suitable alkylating agents can include,for example, an alkyl or aryl sulfonate, an alkyl or aryl halide, or thelike. One or more suitably activated hydroxyls, for example a sulfonateester, and/or one or more suitably activated halides, can be convertedto the corresponding cyano, halo, or amino derivative by displacementwith a nucleophile which can include, for example, a thiol, a cyano, ahalide ion, or an amine (e.g., H₂NR, wherein R is a desiredsubstituent), or the like.

Amines can be obtained by a variety of methods known in the art, forexample, by hydrolysis of one or more amide groups. Amines also can beobtained by reacting one or more suitable oxo groups (e.g., an aldehydeor ketone) with one or more suitable amines under the appropriateconditions, for example, reductive amination conditions, or the like.One or more amines, in turn, can be converted to a number of otheruseful derivatives such as, for example, amides, sulfonamides, and thelike.

Certain chemical modifications of a compound of formula I or II can beintroduced as desired to obtain useful new variants with new or modifiedbiological properties such as: new or improved potency and/orselectivity for inhibiting Ras-mediated biological processes, improvedefficacy against a disease process such as, but not limited to, tumorcell growth, proliferation, survival, invasion and metastasis, as wellas resistance to chemotherapy, other molecularly targeted therapeutics,and radiation, as well as enhanced oral bioavailability, less toxicityin a particular host mammal, more advantageous pharmacokinetics and/ortissue distribution in a given host mammal, and the like. Therefore, thepresent invention employs methods for obtaining useful new compounds offormula I-II by applying one or more well-known chemical reactions to agiven compound to obtain a derivative wherein, for example, one or morephenolic hydroxyl group(s) may instead be replaced by an ester,sulfonate ester or ether group; one or more methyl ether group(s) mayinstead be replaced by a phenolic hydroxyl group; one or more phenolichydroxyl group(s) may instead be replaced by an aromatic hydrocarbonsubstituent; a secondary amine site may instead be replaced by an amide,sulfonamide, tertiary amine, or alkyl quaternary ammonium salt; atertiary amine site may instead be replaced by a secondary amine; andone or more aromatic hydrogen substituent(s) may instead be replaced bya halogen, nitro, amino, hydroxyl, thiol or cyano substituent.

Depending upon the stoichiometric amount of the particular reactant, acompound of formula I or II can be substituted at one, some, or all ofthe respective available positions. For example, when such a compound isreacted with a certain amount of CH₃COCl, an acetate substituent can beintroduced a one, some, or all of the available positions, which mayinclude, for example ether or amino positions.

Other examples may include, but are not limited to: (1) conversion toester, sulfonate ester, and ether substituents at one or more phenolichydroxyl positions in compounds of formula I and II; for instance, forpreparation of esters or sulfonate esters a given compound can bereacted with an acid halide (e.g., RCOX or RSO₂X, where X is Cl, Br orI, and R is a C₁-C₆ aliphatic or aromatic radical) in anhydrous pyridineor triethylamine; alternatively, the given compound may be reacted withan acid (RCO₂H or RSO₃H) wherein R is an aliphatic or aromatic radicaland dicyclohexylcarbodiimide in triethylamine to prepare the ester orsulfonate ester; for preparation of ethers, the given compound isreacted with an organic halide (e.g., RX or RCH₂X, where X is Cl, Br orI, and R is a C₁-C₆ aliphatic or aromatic radical) in anhydrous acetonewith anhydrous potassium carbonate; (2) removal of an ether methylgroup(s) to provide a phenolic hydroxyl functionality and/or conversionof that moiety to an ester, sulfonate, or other ether in a compound orderivative of formula I or II: for instance, for hydrolytic cleavage ofa methyl ether substituent and conversion to a phenolic hydroxyl moiety,the given compound is reacted with BBr₃ or BX₃.(CH₃)₂S in CH₂Cl₂ (whereX is F, Cl or Br); the resulting phenol can be converted to an ester,sulfonate ester or ether as described above; (3) preparation of amide orsulfonamide derivatives at an amine site in a compound of formula I orII: for instance, for preparation of amides or sulfonamide derivatives,the same general procedures described above in (1) apply; in either case(procedure (1) or (3)), an appropriate functional group protectionstrategy (blocking/deblocking of selected group(s)) may need to beapplied; (4) conversion of a secondary amine functionality in a compoundof formula I or II to a tertiary amine: for instance, for preparation ofa tertiary amine, the given compound is reacted with an aldehyde, andthe resulting product is then reduced with NaBH₄; alternatively, forpreparation of an alkyl ammonium salt, the given compound is reactedwith an alkyl halide (RX, where X is Cl, Br or I, and R is a C₁-C₆aliphatic radical) in an anhydrous aprotic solvent; (5) conversion of atertiary amine functionality in a compound of formula I or II to asecondary amine; for instance, for preparation of a secondary amine, thegiven compound is reacted with cyanogen bromide to give a cyanamidederivative which is then treated with LiAlH₄; (6) conversion of one ormore phenolic hydroxyl groups in a given compound of formula I or II toan aromatic hydrogen substituent: for instance, the given compound isconverted (after suitable protection of any amine substituent(s) ifnecessary) to the triflate ester to give the corresponding deoxycompound; (7) substitution of one or more hydrogen substituent(s) on thearyl system(s) on a compound of formula I or II by halogen, nitro,amino, hydroxyl, thiol, or cyano groups: for instance, for preparationof a bromine-substituted derivative, the given compound is reacted withBr₂ in H₂O; for the preparation of other substituted derivatives, thegiven compound is treated with HNO₃/HOAc to provide a nitro-substituted(—NO₂) derivative; in turn, the nitro-derivative can be reduced to anamino derivative, and the amino derivative is the point of origin of thechloro, iodo, cyano, thiol and hydroxyl substitution via well-known andpracticed diazonium substitution reactions. More detailed, specificillustrations of synthesis and derivatization procedures that can beemployed to access any desired member of the family of compoundsrepresented by formulas I and II and derivatives thereof, are providedin the examples that follow herein.

It will be appreciated that certain compounds of formula I or II canhave one or more asymmetric carbon(s) and thus such compounds arecapable of existing as enantiomers or diastereomers. Unless otherwisespecified, the present invention includes such enantiomers ordiastereomers, including any racemates thereof. If desired, the separateenantiomers or diastereomers can be synthesized from appropriate chiralstarting materials, or the racemates can be resolved by conventionalprocedures, which are well-known to those skilled in the art, such aschiral chromatography, fractional crystallization of diastereomers ordiastereomeric salts, and the like. Certain compounds can exist asgeometrical isomers, such as, for example, compounds with double-bondedsubstituents with geometrical isomers Z and E, and the present inventionincludes all such isomers, including certain isomers, for example the Zisomers, which are preferred. Also, certain compounds may containsubstituents wherein there is restricted rotation and/or other geometricisomers are possible. For example, certain oxime substituents may existin syn or anti configurations. The present invention includes all suchconfigurations, including all possible hindered-rotational isomers, andother geometric isomers.

It will be appreciated by one skilled in the art that the proof orconfirmation of the chemical structure of a compound provided by or usedin the present invention can be demonstrated using at least one or morewell-known and established, convergent methods including, but notlimited to, for example: proton and/or carbon NMR spectroscopy, massspectrometry, x-ray crystallography, chemical degradation, and the like.

One or more compound(s) of formula I or II or pharmaceuticallyacceptable salt(s) or prodrugs(s) thereof can be included in acomposition, e.g., a pharmaceutical composition. In that respect, thepresent invention further provides a composition that includes aneffective amount of at least one compound of formula I or II, which maybe in the form of pharmaceutically acceptable salt(s) or prodrug(s)thereof and a pharmaceutically acceptable carrier. The composition ofthe present invention preferably includes a therapeutically orprophylactically effective amount of at least one Ras-inhibitorycompound of formula I or II. The therapeutically or prophylacticallyeffective amount can include an amount that produces a therapeutic orprophylactic response in a patient to whom a compound or composition ofthe present invention is administered. A therapeutically orprophylactically effective amount can include, for example, aRas-inhibitory and/or an anticancer effective amount.

The composition of the present invention can further include atherapeutically or prophylactically effective amount of at least oneadditional compound other than a compound of formula I or II, which mayor may not be another Ras-inhibitory compound, and may be an anticancercompound. When the additional compound is a Ras-inhibitory compoundother than a compound of formula I or II, it is preferably present inthe composition in a Ras-inhibiting amount. When the additional compoundis an anticancer compound in general, it is preferably present in thecomposition in an anticancer effective amount.

The composition of the present invention can be produced by combiningone or more compound(s) of formula I or II with an appropriatepharmaceutically acceptable carrier, and can be formulated into asuitable preparation, which may include, for example, preparations insolid, semi-solid, liquid or gaseous forms such as tablets, capsules,powers, granules, ointments, solutions, suppositories, injections,inhalants, and aerosols, and other formulations known in the art fortheir respective routes of administration. In pharmaceutical dosageforms, a compound of formula I or II can be used alone or in appropriateassociation, as well as in combination, with other pharmacologicallyactive compounds, including other compounds, e.g., other Ras-inhibitorycompounds, as described herein.

Any suitable pharmacologically or physiologically acceptable carrier canbe utilized. The following methods and carriers are merely exemplary andare in no way limiting. In the case of oral preparations, a compound offormula I or II can be administered alone or in combination with atherapeutically or prophylactically effective amount of at least oneother compound. The active ingredient(s) can be combined, if desired,with appropriate additives to make tablets, powders, granules, capsulesor the like.

Suitable additives can include, for example, lactose, mannitol, cornstarch or potato starch. Suitable additives also can include binders,for example crystalline cellulose, cellulose derivatives, acacia, orgelatins; disintegrants, for example, corn starch, potato starch orsodium carboxymethylcellulose; or lubricants such as talc or magnesiumstearate. If desired, other additives such as, for example, diluents,buffering agents, moistening agents, preservatives, and/or flavoringagents, and the like, can be included in the composition.

The Ras-inhibitory compounds used in accordance with the presentinvention can be formulated into a preparation for injection or infusionby dissolution, suspension, or emulsification in an aqueous ornon-aqueous solvent, such as vegetable oil, synthetic aliphatic acidglycerides, esters of higher aliphatic acid or propylene glycol (ifdesired, with conventional additives such as solubilizers isotonicagents, suspending agents, emulsifying agents, stabilizers, andpreservatives).

The compounds of formula I and II also can be made into an aerosolformulation to be administered by inhalation. Such aerosol formulationscan be placed into pressurized acceptable propellants such asdichlorodifluoromethane, propane, nitrogen, and the like.

The compounds can be formulated into suppositories by admixture with avariety of bases such as emulsifying bases or water-soluble bases. Thesuppository formulations can be administered rectally, and can includevehicles such as cocoa butter, carbowaxes, and polyethylene glycols,which melt at body temperature but are solid at room temperature.

Unit dosage forms for oral or rectal administration such as syrups,elixirs, and suspensions can be provided wherein each dosage unit, e.g.,teaspoonful, tablet, or suppository contains a predetermined amount ofthe composition containing the compound of formula I or II. Similarly,unit dosage forms for injection or intravenous administration cancomprise a composition as a solution in sterile water, normal saline, orother pharmaceutically acceptable carrier.

The term “unit dosage form” as used herein refers to physically discreteunits suitable as unitary dosages for human and animal subjects, eachunit containing a predetermined quantity of at least one compound(s) offormula I or II (alone, or if desired, with another therapeutic orprophylactic agent). The unit dosage can be determined by methods knownto those of skill in the art, for example, by calculating the amount ofactive ingredient sufficient to produce the desired effect inassociation with a pharmaceutically acceptable carrier. Thespecifications for the unit dosage forms that can be used in accordancewith the present invention depend on the particular effect to beachieved and the particular pharmacodynamics associated with thecompound(s) in the individual host.

Pharmaceutically acceptable carriers, for example, vehicles, adjuvants,excipients, or diluents, are accessible to those of skill in the art andare typically available commercially. One skilled in the art can easilydetermine the appropriate method of administration for the exactformulation of the composition being used. Any necessary adjustments indose can readily be made by an ordinarily skilled practitioner toaddress the nature or severity of the condition being treated.Adjustments in dose also can be made on the basis of other factors suchas, for example, the individual patient's overall physical health, sexage, prior medical history, and the like.

The compounds of formula I and II can be utilized in a variety oftherapeutic and prophylactic (disease preventing) applications, and alsoin certain non-therapeutic or non-prophylactic applications. It will beappreciated that one or more of these compounds can be used, forexample, as a control in diagnostic kits, bioassays, or the like.Preferably the method of the present invention is appliedtherapeutically or prophylactically, for example, toward treatment orprevention of cancer or toward treatment or prevention of a condition(e.g. an abnormal condition or disease) treatable by the inhibition ofRas-mediated biological process(es). The compounds of formula I and IIcan be administered alone, or in combination with a therapeutically orprophylactically effective amount of at least one additional compoundother than a compound of formula I or II.

Accordingly, the present invention further provides a method oftherapeutically or prophylactically treating a condition treatable bythe inhibition of one or more Ras-mediated biological processes, whichmethod includes administering to a patient a Ras-inhibiting amount of atleast one Ras-inhibitory compound of formula I or II. More particularly,the present invention provides a method of therapeutically orprophylactically treating a condition treatable by the inhibition of oneor more Ras-mediated biological processes, which includes administeringa Ras-inhibiting effective amount of at least one compound of formula Ior II.

A number of conditions can be treated in accordance with the method ofthe present invention. The compounds of formulas I and II, and theircompositions can be used medically to regulate biological phenomena,including but not limited to such Ras-modulated processes as tumor cellgrowth, proliferation, survival, invasion and metastasis, as well asresistance to chemotherapy, other molecularly targeted therapeutics, andradiation. The compounds of formula I and II are therefore useful in thetreatment of diseases and conditions that can be controlled by theinhibition of Ras-mediated cellular functions. Such diseases include,for example, diseases wherein hyperactive Ras (e.g., including mutantRas) is implicated; such diseases prominently include cancer, amongothers. Compounds of formula I or II can be expected to have efficaciousactions in patients with cancer, especially in patients whose cancershave underlying hyperactive, over-expressed or mutant Ras-mediatedpathological processes that are inhibited by a compound(s) of formula Ior II. Other aberrant Ras-mediated diseases or conditions that areexpected to be treatable or preventable by administration ofRas-inhibiting amounts of compound(s) of formula I or II include forexample, neurofibromatosis and Costello syndrome. In the instance ofcancer particularly, compound(s) of formula I or II may promote broadersensitivity of cancer to other drugs and/or radiation therapy byinhibiting the ability of cancer cells to develop or express resistanceto such drugs and/or radiation therapy making possible the effectivechemotherapeutic and/or radiotherapeutic treatment of cancer.

In accordance with an embodiment of the method of the presentintervention, it is preferred that a Ras-inhibiting effective amount isused. In that regard, it is preferred that the Ras-inhibiting amount iseffective to inhibit one or more conditions selected from the groupconsisting of tumor cell growth, proliferation, survival, invasion andmetastasis, as well as resistance to chemotherapy, other molecularlytargeted therapeutics, and radiation.

The method of the present invention further includes administering aRas-inhibiting effective amount of at least one additional compoundother than a compound of formula I or II. In some instances, the methodof the present invention can be made more effective by administering oneor more other Ras-inhibitory compound(s), along with a compound offormula I or II. One or more Ras-inhibitory compound(s) of formula I orII also can be co-administered in combination with an anticancer agentother than a compound of formula I or II, for example, to causeanticancer chemotherapy-resistant and/or radiation-resistant tumor cellsto become chemotherapy-sensitive and/or radiation-sensitive and/or toinhibit de novo the development of cancer cell resistance to theanticancer agent and/or to cancer cell resistance to radiationtreatment.

In accordance with an embodiment of the method, the patient ispre-selected by utilizing an assay of said patient's tissue, blood ortumor for an abnormal, mutant or hyperactive ras gene or Ras protein, oran aberrant Ras-mediated biological process.

In accordance with the methods of the present invention, one or morecompounds of formula I or II can be administered by any suitable routeincluding, for example, oral or parenteral, including intravenous,subcutaneous, intraarterial, intraperitoneal, ophthalmic, intramuscular,buccal, rectal, vaginal, intraorbital, intracerebral, intracranial,intraspinal, intraventricuclar, intrathecal, intracisternal,intracapsular, intrapulmonary, intranasal, transmucosal, transdermal, orvia inhalation. For example, one or more compound(s) of formula I or IIcan be administered as a solution that is suitable for intravenousinjection or infusion, or can be administered as a tablet, a capsule, orthe like, in any other suitable composition or formulation as describedherein. Accordingly, there is a wide variety of suitable formulations ofthe pharmaceutical composition of the present invention. Theformulations may also be applied topically.

The Ras-“inhibiting-effective amount” as utilized in accordance with anembodiment of the composition and method of the present invention,includes the dose necessary to achieve a Ras-“inhibiting effectivelevel” of the active compound in an individual patient. TheRas-inhibiting-effective amount can be defined, for example, as thatamount required to be administered to an individual patient to achievein said patient a Ras-inhibiting-effective blood or tissue level, and/orintracellular target-inhibiting level of a compound of formula I or IIto cause the desired medical treatment.

By way of example and not intending to limit the invention, the dose ofthe pharmaceutically active agent(s) described herein for methods ofpreventing or treating a disease or disorder can be, in embodiments,about 0.001 to about 1 mg/kg body weight of the subject being treatedper day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg,0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day. In certainembodiments, the dose of the pharmaceutically active agent(s) describedherein can be about 1 to about 1000 mg/kg body weight of the subjectbeing treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500mg, 750 mg, or 1000 mg/kg body weight per day.

The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well aswords stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, prevention, amelioration, or inhibition. Rather,there are varying degrees of treatment, prevention, amelioration, andinhibition of which one of ordinary skill in the art recognizes ashaving a potential benefit or therapeutic effect. In this respect, theinventive methods can provide any amount of any level of treatment,prevention, amelioration, or inhibition of the disorder in a mammal. Forexample, a disorder, including symptoms or conditions thereof, may bereduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,or 10%. Furthermore, the treatment, prevention, amelioration, orinhibition provided by the inventive method can include treatment,prevention, amelioration, or inhibition of one or more conditions orsymptoms of the disorder, e.g., cancer. Also, for purposes herein,“treatment,” “prevention,” “amelioration,” or “inhibition” can encompassdelaying the onset of the disorder, or a symptom or condition thereof.

When the effective level is used as the preferred endpoint for dosing,the actual dose and schedule can vary depending, for example, uponinter-individual differences in pharmacokinetics, drug distribution,metabolism, and the like. The effective level also can vary when one ormore compound(s) of formula I or II are used in combination with othertherapeutic agents, for example, one or more additional anticancercompound(s), or a combination thereof. Moreover, the effective level canvary depending upon the particular disease (e.g., cancer orneurofibromatosis) or biological process (e.g., tumor cell growth,proliferation, survival, invasion and metastasis, as well as resistanceto chemotherapy, other molecularly targeted therapeutics, and radiation)for which treatment is desired. Similarly, the effective level can varydepending on whether the treatment is for therapy or prevention of aparticular disease such as, for example, cancer.

Compounds of formula I and II can be expected to be broadly efficaciousanticancer agents, which will inhibit or destroy human solid tumors, andas well non-solid cancer such as leukemias and certain lymphomas. Solidtumors may include particularly those tumors where ras gene mutationsare highly prevalent, such as pancreatic cancer, lung cancer and coloncancer, as well as diverse other solid tumors such as, for example,melanoma, ovarian cancer, renal cancer, prostate cancer, head and neckcancer, endocrine tumors, uterine cancer, breast cancer, sarcomas,gastric cancer, hepatic cancer, esophageal cancer, central nervoussystem (e.g., brain) cancer, hepatic cancer, germline cancer, and thelike.

In a preferred embodiment of the present invention, patients who aremost likely to have a favorable response to a Ras-inhibitory compound offormula I or II can be pre-selected, prior to said treatment with saidcompound, by assaying said patient's blood, tissues or tumor for thepresence ras gene mutations and/or abnormal Ras proteins and/or aberrantRas-mediated biological function(s), using assay procedures (includinguse of commercially available assay kits) well-known to those ofordinary skill in the art.

Accordingly, the present invention further provides a method oftherapeutically or prophylactically treating cancer, which methodcomprises administering to a patient in need thereof an anticancereffective amount of at least one Ras-inhibitory compound(s) of formula Ior II. The anticancer effective amount can be determined, for example,by determining an amount to be administered effective to produce aRas-inhibiting-effective blood or tissue level and/or intracellulartarget-inhibiting “effective level” in the subject patient. Theeffective level can be chosen, for example, as that blood and/or tissuelevel (e.g., 10⁻¹²-10⁻⁶ M from examples that follow) effective toinhibit the proliferation of tumor cells in a screening assay.Similarly, the effective level can be determined, for example, on thebasis of the blood, tissue or tumor level in a patient that correspondsto a concentration of a therapeutic agent that effectively inhibits thegrowth of a human cancer in any assay that is clinically predictive ofanticancer activity. Further, the effective level can be determined, forexample based on a concentration at which certain markers of cancer in apatient's blood or tumor tissue (e.g., mutant or hyperactive ras gene(s)and/or Ras protein(s) and/or aberrant Ras-mediated biologicalpathway(s)) are inhibited by a particular compound that inhibits cancer.Alternatively, the effective level can be determined, for example, basedon a concentration effective to slow or stop the growth of a patient'scancer, or cause a patient's cancer to regress or disappear, or render apatient asymptomatic to a particular cancer, or improve a cancerpatient's subjective sense of condition. The anticancer effective levelcan then be used to approximate (e.g., by extrapolation) or even todetermine precisely, the level which is required clinically to achieve aRas-inhibiting-effective blood, tissue, tumor and/or intracellular levelto cause the desired medical treatment. It will be appreciated that thedetermination of the therapeutically effective amount clinicallyrequired to effectively inhibit Ras-mediated processes also requiresconsideration of other variables that can influence the effective level,as discussed herein. When a fixed effective amount is used as apreferred endpoint for dosing, the actual dose and dosing schedule fordrug administration can vary for each patient depending upon factorsthat include, for example, inter-individual differences inpharmacokinetics, drug absorption, drug disposition and tissuedistribution, drug metabolism, drug excretion, whether other drugs areused in combination, or other factors described herein that influencethe effective level.

One skilled in the art and knowing and understanding the disclosures ofthe present invention can readily determine the appropriate dose,schedule, or method of administering a particular formulation, in orderto achieve the desired effective level in an individual patient. Giventhe disclosures herein, one skilled in the art also can readilydetermine and use an appropriate indicator of the effective level of thecompound(s) of formula I and II. For example, the effective level can bedetermined by direct analysis (e.g., analytical chemistry) or byindirect analysis (e.g., with clinical chemistry indicators) ofappropriate patient samples (e.g., blood and/or tissues). The effectivelevel also can be determined, for example, if the compound in questionhas antitumor activity, by direct or indirect observations, such as, forexample, observing the shrinkage, slowing or cessation of growth orspreading of a tumor in a cancer patient. There are many references tothe art that describe the protocols used in administering and monitoringresponses to active compounds in a patient in need thereof. For example,drug-appropriate protocols used in the administration of different typesof anticancer agents to patients are described in “Cancer Chemotherapyand Biotherapy: Principles and Practice” eds. Chabner and Longo,Lippincott, Williams and Wilkins (2011), and citations therein.

The present inventive method of therapeutically or prophylacticallytreating cancer further includes administering an anticancer effectiveamount of at least one additional compound other than a compound offormula I or II. For example, one or more compound(s) of formula I or IIcan be co-administered with an anticancer agent, and/or can beco-administered with radiation therapy, in which case the effectivelevel is the level needed to inhibit or reverse the ability of thecancer to develop resistance to the anticancer agent and/or to theradiation therapy, respectively.

Examples of anticancer compounds include reversible DNA binders, DNAalkylators, and DNA strand breakers. Examples of suitable reversible DNAbinders include topetecan hydrochloride, irinotecan (CPT11—Camptosar),rubitecan, exatecan, nalidixic acid, TAS-103, etoposide, acridines(e.g., amsacrine, aminocrine), actinomycins (e.g., actinomycin D),anthracyclines (e.g., doxorubicin, daunorubicin), benzophenainse, XR11576/MLN 576, benzopyridoindoles, Mitoxantrone, AQ4, Etopside,Teniposide, (epipodophyllotoxins), and bisintercalating agents such astriostin A and echinomycin.

Examples of suitable DNA alkylators include sulfur mustard, the nitrogenmustards (e.g., mechlorethamine), chlorambucil, melphalan,ethyleneimines (e.g., triethylenemelamine, carboquone, diaziquone),methyl methanesulfonate, busulfan, CC-1065, duocarmycins (e.g.,duocarmycin A, duocarmycin SA), metabolically activated alkylatingagents such as nitrosoureas (e.g., carmustine, lomustine,(2-chloroethyl)nitrosoureas), triazine antitumor drugs such astriazenoimidazole (e.g., dacarbazine), mitomycin C, leinamycin, and thelike.

Examples of suitable DNA strand breakers include doxorubicin anddaunorubicin (which are also reversible DNA binders), otheranthracyclines, belomycins, tirapazamine, enediyne antitumor antibioticssuch as neocarzinostatin, esperamicins, calicheamicins, dynemicin A,hedarcidin, C-1027, N1999A2, esperamicins, zinostatin, and the like.

Examples of anticancer agents include abarelix, aldesleukin,alemtuzumab, altretamine, amifostine, aminoglutethimide, anastrazole,arsenic trioxide, asparaginase, azacitidine, azathioprine, BCG vaccine,bevacizumab, bexarotene, bicalutamide, bleomycin sulfate, bortezomib,bromocriptine, busulfan, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, chloroquine phosphate, cladribine,cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin,daunorubicin hydrochloride, daunorubicin citrate liposomal, dexrazoxane,docetaxel, doxorubicin hydrochloride, doxorubicin hydrochlorideliposomal, epirubicin hydrochloride, estramustine phosphate sodium,etoposide, estretinate, exemestane, floxuridine, fludarabine phosphate,fluorouracil, fluoxymesterone, flutamide, fulvestrant, gefitinib,gemcitabine hydrochloride, gemtuzumab ozogamicin, goserelin acetate,hydroxyurea, idarubicin hydrochloride, ifosfamide, imtinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan hydrochloridetrihydrate, letrozole, leucovorin calcium, leuprolide acetate,levamisole hydrochloride, lomustine, lymphocyte immune anti-thymocyteglobulin (equine), mechlorethamine hydrochloride, medoxyprogestoneacetate, melphalan, mercaptopurine, mesna, methotrexate, mitomycin,mitotane, mitoxantrone hydrochloride, nilutamide, oxaliplatin,paclitaxel, pegaspargase, pentostatin, plicamycin, porfimer sodium,procarbazine hydrochloride, streptozocin, tamoxifen citrate,temozolomide, teniposide, testolactone, testosterone propionate,thioguaine, thiotepa, topotecan hydrochloride, tretinoin, uracilmustard, valrubicin, vinblastine sulfate, vincristine sulfate, andvinorelbine.

Suitable forms of radiation therapy include, for example, all forms ofradiation therapy approved for commercial use in the United States, andthose forms that will become approved in the future, for which radiationresistance thereto can be controlled by a Ras-inhibitory compound offormula I or II.

In accordance with an embodiment of the methods of the presentinvention, prophylaxis includes inhibition as described herein, e.g.,inhibition of the growth or proliferation of cancer cells, or inhibitionof aberrant Ras-mediated cellular functions. The inhibition can be, butneed not be, 100% inhibition in order to be prophylactically effective,and a clinically desirable benefit can be realized with less than 100%inhibition.

The particular Ras-inhibitory compound(s) of formula I or II used inaccordance with the present invention can be selected based upon thepotency and/or selectivity for inhibiting Ras-mediated cellularprocesses, as assessed by in vitro or in vivo assays, and/or based onother pharmacological, toxicological, pharmaceutical or other pertinentconsiderations that are well-known to those skilled in the art. Routinemethods for the specific bioassay, quantitation and comparisons ofRas-inhibitory inhibitory and other biological activities and propertiesof compounds of formula I and II in various tissues, cells, organellesand other preparations, as well as in vivo testing in animals arewell-documented in the literature (e.g., see Teicher and Andrews (eds.),Anticancer Drug Development Guide, Humana (2004), and various authorsand chapters therein). More specific illustrations of these and otherdetails pertinent to enablement of the present invention are provided inthe examples which follow.

The following examples further illustrate the invention but, of course,should not be construed as in any way limiting its scope.

Example 1

This example illustrates the synthesis of a compound in accordance withan embodiment of the invention:(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(007).

(A) p-fluoro-α-methylcinnamic acid: p-Fluorobenzaldehyde (200 g, 1.61mol), propionic anhydride (315 g, 2.42 mol) and sodium propionate (155g, 1.61 mol) in a 1 L three-necked flask in an atmosphere of argon wasstirred in an oil bath to 140° C. for 36 hours. The clear solution wascooled to 100° C. and poured into 8 L of water. The precipitate wascollected and dissolved by adding potassium hydroxide to 2 L of icewater to pH 12. The aqueous solution was extracted with ether, and theextracts washed with potassium hydroxide solution (200 mL×2). Thecombined aqueous solution was acidified with concentrated HCl. Theprecipitate was collected by filtration, washed with water, ethanol andhexane, dried under air to give p-fluoro-α-methylcinnamic acid, whichwas used for next step reaction without further purification.

(B) p-Fluoro-α-methylhydrocinnamic acid: A 2 L catalytic hydrogenationflask containing p-fluoro-α-methylcinnamic acid (180 g, 0.987 mol),5%-Pd/C (1.2 g) and 1.2 L ethanol was flushed with argon and warmed to65-70° C. The mixture was treated with hydrogen (40 psi) until thehydrogen uptake ceases (about 30 min). The catalyst was filtered off,and the filtrate was concentrated in vacuum to givep-fluoro-α-methylhydrocinnamic acid as an oil.

(C) 5-fluoro-2-methylindanone: Polyphosphoric acid (PPA 85%, 650 g) waswarmed in a 80° C. water bath for 1 h, then transferred to a 1 L3-necked flask equipped with a mechanical stirrer, a dropping funnel,and a thermometer. The flask was warmed in a 70° C. oil bath andp-fluoro-α-methylhydrocinnamic acid (93.2 g, 0 5 mol) was added in about5 minutes with stirring. The temperature was gradually raised to 90° C.,and kept there for about 30 min. The reaction mixture was poured into 2L of ice water, the aqueous layer extracted with ether, and the solutionwashed twice with saturated sodium chloride solution, 5% Na₂CO₃solution, water, dried over Na₂SO₄, and then concentrated to give amilky oil. The oil was dissolved in 100 mL of methylene chloride and 200mL of hexane, and the solution was loaded to a dry-packed silica gelflash column (800 g of TLC grade silica gel tightly packed in a 2 Lfritted funnel, vacuum), eluted with 5% ether-hexane to give5-fluoro-2-methylindanone as a clear oil.

(D) 5-fluoro-2-methylindenyl-3-acetic acid: A mixture of5-fluoro-2-methylindanone (184 g, 1.12 mol), cyanoacetic acid (105 g,1.23 mol), acetic acid (130 g), and ammonium acetate (34 g) in drytoluene (about 600 ml) was refluxed for 48 to 72 hours, and theliberated water/acetic acid was collected in a Dean Stark trap. To thecooled reaction mixture was added 600 mL of methylene chloride, thesolution washed with water (200 mL×3), the organic layer concentrated,and the residue treated with 150 g of potassium hydroxide in 300 ml ofethanol and 200 ml of water. The mixture was refluxed overnight undernitrogen, the ethanol removed under vacuum, 500 ml water added, theaqueous solution washed well with ether and then boiled with charcoal.The aqueous filtrate was acidified to pH 2 with 50% hydrochloric acid,and extracted with methylene chloride (300 mL×3). The solvent wasevaporated, and the residue treated with acetone in a sonicator bathuntil precipitate formed. The mixture was stored in a −20° C. freezerovernight, and the precipitate collected by filtration. The proceduregave 5-fluoro-2-methylindenyl-3-acetic acid as a colorless solid (mp164-166° C.).

(E)(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid: The 5-fluoro-2-methyl-3-indenylacetic acid (0.54 g, 2.62 mmol),4-acetoxy-3,5-dimethoxybenzaldehyde (0.60 g, 2.67 mmol) and potassiumbutoxide (0.69 g, 7.7 mmol) in DMSO (6 ml) were stirred in a microwavesynthesizer at 75° C. under argon for 2 h. After cooling, the reactionmixture was poured into 50 ml of ice-water, and was acidified with 2Nhydrochloric acid. The mixture was extracted with methylene chloride (25mL×2), the combined organic layer washed with water (25 mL×2), andconcentrated. The residue was purified on a silica gel column threetimes to produce the titled compound (E, 117 mg) as a yellow/orangesolid.

(F)(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(007): The(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (120 mg, 0.324 mmol), 1,1′-Carbonyldiimidazole (100 mg, 0.61 mmol)in 5 mL of anhydrous methylene chloride was stirred for 30 min at roomtemperature. Furfuryl amine (100 μL, 1.13 mmol) was added, the reactionmixture stirred for 2 h, and quenched with 1 ml of 30% potassiumhydroxide solution, which was diluted with 25 mL of methylene chloride,neutralized with 2 mL of acetic acid, washed with water (20 mL×3), driedwith sodium sulfate, then concentrated. The residue was purified withsilica gel column, eluted with hexane/acetone. The major yellow fractionwas collected and after concentration the residue (120 mg) was storedunder argon in a freezer, and after 2 weeks crystals formed. The mixturecontaining the crystals was suspended in 2 mL of ethyl ether and 3 mL ofhexane, treated with sonicator for 1 h, then stored in a −20° C. freezerovernight. The precipitate was collected by filtration, and the titledcompound (007) was obtained as a yellow solid (41 mg).

Example 2

This example illustrates the synthesis of another compound in accordancewith an embodiment of the invention:(Z)-2-(5-methoxy-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(006).

(A) p-methoxy-α-methylcinnamic acid: p-Methoxybenzaldehyde (219 g, 1.61mol), propionic anhydride (315 g, 2.42 mol) and sodium propionate (155g, 1.61 mol) in a 1 L three-necked flask in an atmosphere of argon wasstirred in an oil bath at 140° C. for 36 hours. The clear solution wascooled to 100° C., poured into 8 L of water, and the precipitatecollected and dissolved by adding potassium hydroxide to 2 L of icewater to pH 12. The aqueous solution was extracted with ether, theextracts washed with potassium hydroxide solution (200 mL×2) and thecombined aqueous solution acidified with concentrated HCl. Theprecipitate was collected by filtration, washed with water, ethanol andhexane, then dried over air to give p-methoxy-α-methylcinnamic acid (235g) which was used for next step reaction without further purification.

(B) p-methoxy-α-methylhydrocinnamic acid: A 2 L catalytic hydrogenationflask containing p-methoxy-α-methylcinnamic acid (192 g, 1.00 mol),5%-Pd/C (1.2 g) and 1.2 L ethanol was flushed with argon and warmed to70° C. The mixture was treated with hydrogen (40 psi) until the hydrogenuptake ceased (about 30 min). The catalyst was filtered off, and thefiltrate concentrated in vacuum to give p-methoxy-α-methylhydrocinnamicacid as an oil.

(C) 5-methoxy-2-methylindanone: Polyphosphoric acid (PPA 85%, 650 g) waswarmed in a 60° C. water bath for 1 h, and transferred to a 1 L 3-neckedflask equipped with a mechanical stirrer, a dropping funnel, and athermometer. The flask was warmed to 50° C. in oil bath andp-methoxy-α-methylhydrocinnamic acid (96 g, 0.50 mol) was added in about5 minutes with stirring. The temperature was gradually raised to 70° C.for about 15 min, and the solution was poured into 2 L of ice water. Theaqueous layer was extracted with ether, and the solution was washedtwice with saturated sodium chloride solution, 5% Na₂CO₃ solution,water, dried over Na₂SO₄, and then concentrated to give a milky oil. Theoil was dissolved in 100 mL of methylene chloride and 200 mL of hexane,and applied to a dry-packed silica gel flash column (800 g of TLC gradesilica gel tightly packed in a 2 L fritted funnel, vacuum), eluted with5% ether-petroleum ether to give 6-methoxy-2-methylindanone as a clearoil.

(D) 5-methoxy-2-methylindenyl-3-acetic acid: A mixture of6-methoxy-2-methylindanone (197 g, 1.12 mol), cyanoacetic acid (105 g,1.23 mol), acetic acid (130 g), and ammonium acetate (34 g) in drytoluene (about 600 ml) was refluxed for 48 to 72 hours, until theliberated water collected in a Dean Stark trap ceased. To the cooledtoluene reaction mixture was added 600 mL of methylene chloride. Thesolution was washed with water (200 mL×3), the organic layerconcentrated, and the residue treated with 150 g of potassium hydroxidein 300 ml of ethanol and 200 ml of water. The mixture was refluxedovernight under nitrogen, the ethanol removed under vacuum, 500 ml wateradded, the aqueous solution washed well with ether and then boiled withcharcoal. The aqueous filtrate was acidified to pH 2 with 50%hydrochloric acid, extracted with methylene chloride (300 mL×3), solventevaporated, and the residue treated with acetone in a sonicator bathuntil a precipitate formed. The mixture was stored at −20° C. overnight,and the precipitate collected by filtration. The procedure gave5-methoxy-2-methylindenyl-3-acetic acid as a colorless solid (mp164-166° C.).

(E)(Z)-2-(5-methoxy-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid: 5-methoxy-2-methyl-3-indenylacetic acid (0.50 g, 2.29 mmol),4-acetoxy-3,5-dimethoxybenzaldehyde (0.60 g, 2.67 mmol) and potassiumbutoxide (1.0 g, 8.9 mmol) in anhydrous DMSO (5 ml) and pyridine (10 mL)were stirred at 95° C. under argon for 1 h. The reaction mixture wascooled to 65° C. 1.0 mL of methanol was added and stirred for 30 min.After cooling, the mixture was poured into 50 ml of ice-water, acidifiedwith 2N hydrochloric acid, and extracted with methylene chloride (25mL×2), and the combined organic layer washed with water (25 mL×2), andconcentrated. The residue was purified on a silica gel column twice, thefirst eluted with methylene chloride/methanol, followed by washing withhexane, acetone/acetic acid, to produce the title compound (E, 152 mg)as a yellow/orange solid.

(F)(Z)-2-(5-methoxy-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(006):(Z)-2-(5-methoxy-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (123 mg, 0.324 mmol), 1,1′-carbonyldiimidazole (100 mg, 0.61 mmol)in 5 mL of anhydrous methylene chloride was stirred for 30 min at roomtemperature, furfuryl amine (100 μL, 1.13 mmol) was added, and thereaction mixture stirred for 2 h, then quenched with 1 ml of 30%potassium hydroxide solution. The solution was diluted with 25 mL ofmethylene chloride, neutralized with 2 mL of acetic acid, washed withwater (20 mL×3), dried with sodium sulfate, and concentrated. Theresidue was purified over silica gel, eluted with hexane/acetone, andthe major yellow fraction was collected. After concentrating, theresidue was stored in a freezer under argon until a crystal seed formed(˜2 weeks). The mixture was suspended in 2 mL of ethyl ether and 3 mL ofhexane, treated with sonicator for 1 h, then stored in a −20° C. freezerovernight. The precipitate was collected by filtration. The titlecompound (006) was obtained as a yellow solid (36 mg).

Example 3

This example illustrates the synthesis of compound (019):(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide(019).

(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (120 mg, 0.324 mmol) (see (E) under Example 1 above), and1,1′-carbonyldiimidazole (100 mg, 0.61 mmol) in 5 mL of anhydrousmethylene chloride was stirred for 30 min at room temperature. To thereaction mixture (1-methyl-1H-pyrrol-2-yl)methanamine (110 μL, 1.0 mmol)and 0.5 mL of pyridine were added. The mixture was stirred for 2 h,quenched with 1 ml of 30% potassium hydroxide solution, diluted with 25mL of methylene chloride, neutralized with 2 mL of acetic acid, washedwith water (20 mL×3) and dried with sodium sulfate. The organic layerwas concentrated and the residue was purified with silica gel columneluted with hexane/acetone. The major yellow fraction was collected, andafter concentration the residue was treated with acetone/hexane,sonicated for 1 h, and stored in a −20° C. freezer for 2 h. Theprecipitate was collected by filtration, and the titled compound (019)was obtained as a yellow solid (75 mg).

Example 4

This example illustrates the synthesis of various other exemplarycompounds of formula I. When the same synthetic approach (e.g., SchemeI) is used as illustrated in Examples 1-2, except in theacetamide-forming step (F) using the appropriate precursor acetic acidderivative reacted with one of the following amines to produce thecorresponding amides (designated in parentheses): furfuryl amine (001,008, 012, 013, 014, 016, 017, 020, 021); (1H-pyrrol-2-yl)methanamine(018, 022); and (1-methyl-1H-pyrrol-2-yl)methanamine (019).

Example 5

This example illustrates synthesis of compound (029):(Z)-2-(5-fluoro-1-(4-mesyloxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(029).

(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(007) (139 mg, 0.31 mmol), methanesulfonic anhydride (80 mg, 0.46 mmol)in 3 mL of anhydrous pyridine were stirred at 50° C. for 3 h. Thereaction mixture was quenched with water, diluted with 20 mL ofmethylene chloride, the organic solution washed with 10 mL water threetimes, and concentrated. The residue was purified on a silica gelcolumn, eluted with hexane/acetone. The major yellow fraction wascollected and recrystallized from dichloromethane and hexane to give thetitled compound (029) as a yellow solid (78 mg).

Example 6

This example illustrates the synthesis of another exemplary compound offormula I, specifically(Z)—N-(2-(dimethylamino)ethyl)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)acetamide(026).

(A)(Z)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)aceticacid: 5-Fluoro-2-methyl-3-indenylacetic acid (0.50 g, 2.29 mmol),2-furaldehyde (256 mg, 2.67 mmol) and sodium methoxide (0.40 g) in 5 mLof anhydrous methanol were treated with microwave synthesizer at 85° C.under argon for 1 h. The reaction mixture was cooled to roomtemperature, concentrated, and acidified with acetic acid. The mixturewas dissolved in methylene chloride (35 mL), washed with water (25mL×2), and concentrated. The residue was purified on a silica gel columneluted with hexane and acetone/acetic acid. The titled compound (A, 463mg) was obtained as a yellow solid after crystallization from ethylacetate/hexane.

(B)(Z)—N-(2-(dimethylamino)ethyl)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)acetamide(026).(Z)-2-(5-fluoro-1-(furan-2-ylmethylene)-2-methyl-1H-inden-3-yl)aceticacid (142 mg, 0.500 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.61mmol) in 5 mL of anhydrous methylene chloride was stirred for 30 min atroom temperature. To the solution was added2-N,N-dimethylaminoethylamine (100 μL, 1.13 mmol), followed by stirringfor 45 min. The reaction mixture was quenched with 1 ml of 30% potassiumhydroxide solution, diluted with 25 mL of methylene chloride, washedwith water (20 mL×3), dried over sodium sulfate, and concentrated. Theresidue was purified over silica gel eluted with methylenechloride/methanol. The major yellow fraction was collected andrecrystallized from acetone/ethyl ether. The title compound (026) wasobtained as a yellow solid (152 mg).

Example 7

This example illustrates the synthesis of an exemplary prodrug of acompound of the invention, specifically(Z)-2-(5-fluoro-1-(4-formoxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(002, which is a prodrug of 007).

In a sealed 25 mL round-bottom flask(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide(007) (90 mg, 0.2 mmol) was dissolved in 4 mL of pyridine. Aceticanhydride (0.2 mL) was added. The solution was stirred at 50° C. for 2h. The reaction mixture was quenched with ethanol, concentrated, and theresidue purified on a silica gel column eluted with hexane/acetone. Themajor yellow fraction was collected, and recrystallized fromacetone/hexane to give the title compound (002) as a yellow solid.

Example 8

This example illustrates the synthesis of compound 030 in accordancewith an embodiment of the invention: (S) and (R)(Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide.

(A)(Z)-2-(5-methoxy-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid. To a 500 mL round-bottom flask containing5-methoxy-2-methylindenyl-3-acetic acid (Example 2D) (18.0 g, 0.083mmol), 3,4,5-trimethoxybenzaldehyde (22 g, 0.112 mole), sodium methoxide(14 g, 0.259 mole), 300 mL of anhydrous methanol was added. The flaskwas securely sealed with a septum, and the reaction mixture was stirredin an oil bath at 80-85° C. for 5 h. The reaction mixture was cooled ina freezer for 2 h, the precipitate collected by filtration, and washedwith acetone to give a yellow solid, which was then suspended in 500 mLof dichloromethane, neutralized with hydrochloric acid and washed withwater (200 mL×3). The organic layer was concentrated, and the residuedissolved in 100 mL of acetone, followed by addition of 300 mL ofhexane. The suspension was treated with sonication until a precipitateformed, then stored in freezer for 2 h, and the precipitate collected byfiltration, washed with hexane, dried in vacuum to obtain the titledcompound as a bright yellow solid (22.5 g). Repeating therecrystallization procedure gave a second crop (2.2 g).

(B)(S)—(Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide(S-030).(Z)-2-(5-methoxy-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (20.90 g, 50 mmole), 1,1′-carbonyldiimidazole (10.0 g, 61 mmole) in150 mL of anhydrous methylene chloride was stirred for 30 min at roomtemperature, (S)-1-methylpyrrolidin-3-amine (5.0 mL, 50 mmol) was addedwith 60 mL of anhydrous pyridine. The reaction mixture was stirred for 1h at rt, then the temperature was brought up to 45° C., and stirred for5 h. The reaction was quenched with 15 ml of 30% potassium hydroxidesolution, the mixture diluted with 200 mL of methylene chloride,neutralized with acetic acid to pH 5, washed with water (150 mL×3),dried with sodium sulfate, and concentrated. The residue was purifiedover silica gel eluted with hexane/acetone/methanol, and the majoryellow fraction was collected, treated with 1.1 eq. of hydrogen chloride(4M in dioxane), then concentrated. A 5 mg sample was diluted in theacetone/ethanol and left in the air until crystals formed on the glasswall. The crystal seed was added to the concentrated solution ofacetone/ethanol at −20° C., stored for 48 h, and the precipitate wascollected by filtration to give the titled compound as a yellow solid.Repeating the procedure give second and third crops (14.5 g).

(C)(R)—(Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide(R-030).(Z)-2-(5-methoxy-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (418 mg, 1.00 mmol), 1,1′-carbonyldiimidazole (100 mg, 1.21 mmol)in 8 mL of anhydrous methylene chloride was stirred for 30 min at roomtemperature, (R)-1-methylpyrrolidin-3-amine (0.11 mL, 1.1 mmol) wasadded with 1 mL of anhydrous pyridine. The reaction mixture was stirredfor 1 h at rt, then the temperature was brought up to 45° C., andstirred for 3 h. The reaction was quenched with 1.5 ml of 30% potassiumhydroxide solution, diluted with 20 mL of methylene chloride,neutralized with acetic acid to pH 5, washed with water (15 mL×3), driedwith sodium sulfate, and concentrated. The residue was purified oversilica gel eluted with hexane/acetone/methanol, and the major yellowfraction was collected. The major faction was treated with 1.1 eq. ofhydrogen chloride (4M in dioxane), then concentrated. The residue wascrystallized from acetone/ethanol stored at −20° C. for 48 h. Theprecipitate was collected by filtration to give the titled compound as ayellow solid (65 mg).

Example 9

This example illustrates the synthesis of compound 031 in accordancewith an embodiment of the invention:(RS)—(Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide.

(A)(Z)-2-(5-fluoro-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid. To a 500 mL round-bottom flask containing5-fluoro-2-methylindenyl-3-acetic acid (Example 1D) (18.0 g, 0.087mmol), was added 3,4,5-trimethoxybenzaldehyde (22 g, 0.112 mole), sodiummethoxide (14 g, 0.259 mole) and 300 mL of anhydrous methanol. The flaskwas securely sealed with a septum, and the reaction mixture was stirredin an oil bath at 80-85° C. for 5 h, and cooled in a freezer for 2 h.The precipitate was collected by filtration, washed with acetone to givea yellow solid, which was then suspended in 500 mL of dichloromethane,neutralized with hydrochloric acid and washed with water (200 mL×3). Theorganic layer was concentrated, and the residue dissolved in 100 mL ofacetone, followed by addition of 300 mL of hexane. The suspension wastreated with sonication to initiate precipitate formation, stored infreezer for 2 h, the precipitate was collected by filtration, washedwith hexane, and dried under vacuum to obtain the titled compound as abright yellow solid (21.5 g).

(B)(RS)—(Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpyrrolidin-3-yl)acetamide(031).(Z)-2-(5-fluoro-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (20.40 g, 50 mmole), 1,1′-carbonyldiimidazole (10.0 g, 61 mmole) in150 mL of anhydrous methylene chloride was stirred for 30 min at roomtemperature, then 1-methylpyrrolidin-3-amine (5.0 mL, 50 mmol) was addedwith 60 mL of anhydrous pyridine. The reaction mixture was stirred for 1h at r, then the temperature was brought up to 45° C., and the mixturestirred for 5 h. The reaction was quenched with 15 ml of 30% potassiumhydroxide solution, and then the solution was diluted with 200 mL ofmethylene chloride, neutralized with acetic acid to pH 5, washed withwater (150 mL×3), dried with sodium sulfate, and concentrated. Theresidue was purified over silica gel eluted withhexane/acetone/methanol, and the major yellow fraction was collected,treated with 1.1 eq. of hydrogen chloride (4M in dioxane), andconcentrated. The residue was recrystallized from acetone/ethanol togive the titled compound as a yellow solid (13.6 g).

Example 10

This example illustrates the synthesis of compound 032 in accordancewith an embodiment of the invention:(RS)—(Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide.

(Z)-2-(5-methoxy-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (see (A) under synthesis of 030, above) (209 mg, 0.50 mmole), and1,1′-carbonyldiimidazole (100 mg, 0.61 mmole) in 10 mL of anhydrousmethylene chloride was stirred for 30 min at room temperature, then1-methylpiperidin-3-amine (0.6 mmol) was added with 1.0 mL of anhydrouspyridine. The reaction mixture was stirred for 1 h at rt, then thetemperature was brought up to 45° C., and the mixture stirred for 2 h.The reaction was quenched with 1 ml of 30% potassium hydroxide solution,the solution diluted with 20 mL of methylene chloride, neutralized withacetic acid to pH 5, washed with water (10 mL×3), dried on sodiumsulfate, and concentrated. The residue was purified over silica geleluted with hexane/acetone/methanol, and the major yellow fraction wascollected, treated with 0.2 mL of hydrogen chloride (4M in dioxane), andconcentrated. The residue was recrystallized from acetone/ethanol togive the titled compound as a yellow solid (101 mg).

Example 11

This example illustrates synthesis of compound 033 in accordance with anembodiment of the invention:(RS)—(Z)-2-(5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-(1-methylpiperidin-3-yl)acetamide.

(Z)-2-(5-fluoro-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (see (A) under synthesis of 031, above) (204 mg, 0.50 mmol), and1,1′-carbonyldiimidazole (100 mg, 0.61 mmole) in 10 mL of anhydrousmethylene chloride was stirred for 30 min at room temperature, then1-methylpiperidin-3-amine (0.6 mmol) was added with 1.0 mL of anhydrouspyridine. The reaction mixture was stirred for 1 h at rt, then thetemperature was brought up to 45° C., and the mixture stirred for 2 h.The reaction was quenched with 1 ml of 30% potassium hydroxide solution,and the solution was diluted with 20 mL of methylene chloride,neutralized with acetic acid to pH 5, washed with water (10 mL×3), driedon sodium sulfate, and concentrated. The residue was purified oversilica gel eluted with hexane/acetone/methanol, and the major yellowfraction was collected, treated with 0.2 mL of hydrogen chloride (4M indioxane), and concentrated. The residue was recrystallized fromacetone/ethanol to give the titled compound as a yellow solid (86 mg).

Example 12

This example illustrates synthesis of additional exemplary compounds ofthe present invention, particularly compounds 130, 131, 132, 133, 134,135, 138, 139, 141, 143, 144, 145, 151, 152 and 155 (the synthesis of154 was illustrated previously herein, under Scheme III). Thesecompounds were chosen to further illustrate and reinforce that extensivevariations in substituents on the aryl and heteroaryl rings, andvariations of E, R′ and R″ can be achieved readily using methods wellknown to those of ordinary skill in the art. The synthesis schemes belowall start with the key intermediate, the desired substituted orunsubstituted indenyl acetic acid, synthesis of which is illustrated indetail in previous examples herein.

Synthesis of Compound 130:

Synthesis of Compound 131:

Synthesis of Compound 132:

Synthesis of Compound 133:

Synthesis of Compound 134:

Synthesis of Compound 135:

Synthesis of Compound 138:

Synthesis of Compound 139:

Synthesis of Compound 141:

Synthesis of Compound 143:

Synthesis of Compound 144:

Synthesis of Compound 145:

Synthesis of Compound 151:

Synthesis of Compound 152:

Synthesis of Compound 155:

Example 13

This example illustrates a synthesis of a representative compound (210)of formula I or II having no hydrogen substituent on the amide nitrogen;and, this also illustrates a benzoyl ester derivative compound (209)which is an example of a prodrug of 210.

(A) To a stirred mixture of(Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-indene-3-yl)aceticacid (370 mg, 1 mmol), sodium hydroxide (160 mg, 4 mmol), and H₂O (10mL), benzoyl chloride (1 mmol) was added dropwise at 0° C. The reactionmixture was stirred for 2 hrs, acidified, filtered, the precipitateextracted with 20 ml hot water and the insoluble part was recrystallizedfrom ethylacetate-hexane to give(Z)-2-(1-(4-(benzoyloxy)-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)aceticacid in 70% yield.

(B) To a stirred solution of(Z)-2-(1-(4-(benzoyloxy)-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)aceticacid (100 mg, 0.21 mmol) in dichloromethane (5 ml), 1,1′-carbonyldiimidazol (38 mg, 0.23 mmol) was added in one portion resulting in theevolution of CO₂ gas. The solution was stirred for 20 minutes, thenN-methyl furfurylamine (28 mg, 0.25 mmol) and pyridine (3 ml) was added,and the reaction mixture was heated to 45° C. for 3 hrs. Solvent wasremoved under vacuum and the residue was extracted with dichloromethane,then the organic layer was washed with water, brine and dried (anhydrousMgSO₄). The filtered organic layer was evaporated under vacuum and theresidue was purified by silica column chromatography eluting withhexane-acetone (1:1). The product (209) was recrystallized fromEtOAc-hexane in 65% yield as a yellow solid.

(C) Compound 209 (35 mg) was dissolved in methanolic ammonia (12 mL, 7N)and was stirred overnight. Solvent was evaporated under vacuum and theresidue was purified by silica column chromatography by eluting withhexane-acetone (1:1). The product compound (210) was recrystallized fromethyl acetate-hexane as a yellow solid (55% yield).

Example 14

This example illustrates typical synthesis schemes for making variousexemplary prodrug compounds having formula I or II. Given thedisclosures of the invention, one of ordinary skill in the art can useor adapt as necessary such schemes as shown below to make certaindesired prodrugs or other derivative compounds having formula I or II ofthe invention.

Synthesis of Compound 320:

Such a scheme as used for compound 320 can be adapted to make otherexemplary compounds having formula I or II, such as 214, 301, 330 and340.

Synthesis of Compound 321:

Such a scheme as used for compound 321 can be adapted to make otherexemplary compounds having formula I or II, such as 302, 311, 331 and341.

Synthesis of Compound 323:

Such a scheme as used for compound 323 can be adapted to make otherexemplary compounds having formula I or II, such as 300, 312, 332, 342,350, 352, 303, 313, 333 and 343.

Synthesis of Compound 324:

Such a scheme as used for compound 324 can be adapted to make otherexemplary compounds having formula I or II, such as 304, 314, 334 and344.

Synthesis of Compound 325:

Such a scheme as used for compound 325 can be adapted to make otherexemplary compounds having formula I or II, such as 305, 315, 335 and345.

Synthesis of Compound 326:

Such a scheme as used for compound 326 can be adapted to make otherexemplary compounds having formula I or II, such as 306, 316, 336, 346,351, 353 and 355. Synthesis of compound 327:

Such a scheme as used for compound 327 can be adapted to make otherexemplary compounds having formula I or II, such as 307, 317 and 347.

Synthesis of Compound 328:

Such a scheme as used for compound 328 can be adapted to make otherexemplary compounds having formula I or II, such as 308, 318, 338 and348.

Synthesis of Compound 329:

Such a scheme as used for compound 329 can be adapted to make otherexemplary compounds having formula I or II, such as 309, 319, 339 and349.

Example 15

This example illustrates the synthesis of additional exemplary compoundsof the present invention, in particular compounds 095, 096 and 097.

The synthesis of(Z)—N-(furan-2-ylmethyl)-2-(1-(4-ethoxycarbonyl-3,5-dimethoxybenzylidene)-5-methoxy-2-fluoro-1H-inden-3-yl)acetamide(095) is as follows. A solution of 3,4,5-trimethoxybenzaldehyde dimethylketal (4 mmol) in anhydrous THF (5 mL) was added dropwise to asuspension of freshly cut sodium (0.0012 g-atom) in anhydrous THF (30mL) under dry Ar). The mixture was stirred at room temperature for 24 h,then chilled to −40° C. Ethyl chloroformate (4.2 mmol) in 3 mL of THFwas added dropwise and stirred for 5 h, followed by quenching by slowaddition of 1 mL water. The mixture was neutralized with 2 mL of aceticacid, concentrated, and the residue dissolved in methylene chloride (100mL), washed with water (50 mL×2), and concentrated. The residue waspurified over silica gel eluted with acetone/hexane, recrystallized fromacetone/hexane to give 3,5-dimethoxyl-4-methoxycarbonyl-benzaldehydedimethyl ketal as colorless crystals, and treated with 6M HCl to afford3,5-dimethoxyl-4-methoxycarbonyl-benzaldehyde as a colorless solid. Thisaldehyde (0.60 g), along with 5-fluoro-2-methylindenyl-3-acetic acid(0.54 g), and sodium methoxide (0.42 g) in 8 mL of anhydrous methanolwas treated in a microwave synthesizer at 85° C. for 2 h. The mixturewas transferred to a beaker containing 15 mL acetone and 15 ml of ethylether, and the precipitate was collected, neutralized with acetic acid,purified over silica gel eluted with hexane and acetone, andrecrystallized from acetone/hexane to give the(Z)-2-(5-fluoro-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid as a yellow solid (0.62 g). A solution of this acid (120 mg) andcarbonyldiimidazole (100 mg) in 6 mL of anhydrous methylene chloride wasstirred for 30 min, then furfuryl amine (150 μL) was added, and stirredfor 2 h at room temperature. Following recrystallization, 126 mg of 095was obtained as a yellow solid.

The synthesis of(Z)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide(096) is as follows. A solution of(Z)-2-(5-methoxy-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (120 mg) and carbonyldiimidazole (100 mg) in 6 mL of anhydrousmethylene chloride was stirred for 30 min, followed by addition of1-methyl-1H-pyrrol-2-yl)methylamine (50 μL) and 2 mL of anhydrouspyridine. The reaction solution was stirred for at 50° C. for 2 h,quenched with water, diluted with 50 mL of methylene chloride, washedwith water (20 mL×3), and concentrated. The residue was purified on asilica gel column, recrystallized from acetone/ethyl ether to afford 47mg of 096 as a yellow solid.

The synthesis of(Z)—N-((1H-pyrrol-2-yl)methyl)-2-(5-methoxy-2-methyl-1-(3,4,5-trimethoxybenzylidene)-1H-inden-3-yl)acetamide(097) is as follows. A solution of(Z)-2-(5-methoxy-1-(3,4,5-trimethoxybenzylidene)-2-methyl-1H-inden-3-yl)aceticacid (120 mg) and carbonyldiimidazole (100 mg) in 6 mL of anhydrousmethylene chloride was stirred for 30 min, followed by addition of(1H-pyrrol-2-yl) methylamine (50 μL) and 2 mL of anhydrous pyridine. Thereaction solution was stirred for at 50° C. for 2 h, quenched withwater, diluted with 50 mL of methylene chloride, washed with water (20mL×3), and concentrated. The residue was purified the on a silica gelcolumn, and recrystallized from acetone/ethyl ether to afford 47 mg of097 as a yellow solid.

Example 16

This example illustrates synthesis of a medically useful compound offormula I or II wherein a substitution is made at R and/or R₀ of anexisting compound of formula I or II. Here, for example, a newsubstituent is introduced at R or R₀ of compound 007. To a solution of007 (120 mg, 0.27 mmol) in dichloromethane (20 ml) at −15° C., adichloromethane solution of DDQ (30 mg, 0.14 mmol, 12 ml) was slowlyadded under argon. The reaction mixture was stirred at 0-4° C. for 10min, then diluted with hexane, followed by silica column chromatographyeluted with hexane-acetone (1:1). The major fraction was recrystallizedas an orange solid from acetone-hexane, and 50 mg of this material wasdissolved in ethanol (2 ml), followed by addition of benzylamine (18 mg,0.16 mmol) and acetic acid (0.01 mL). The reaction was stirred at 85° C.for 6 hrs. and the solvent removed under vacuum. The residue waspurified by silica column chromatography eluting with hexane-acetone(1:1) and methylene chloride-methanol to afford 202 as a yellow solid inoverall 40% yield.

In another illustration, to a solution of 007 (120 mg, 0.27 mmol) indichloromethane (20 ml) at 15° C., a dichloromethane solution of DDQ (30mg, 0.14 mmol, 12 ml) was slowly added under argon. The reaction mixturewas stirred at 0-4° C. for 10 min, then diluted with hexane, followed bysilica column chromatography eluted with hexane-acetone (1:1). An orangesolid was recrystallized from acetone-hexane, and 50 mg of this materialwas dissolved in ethanol (2 ml), followed by addition ofpyridine-4-ylmethanamine (21 mg, 0.2 mmol) along with a catalyticquantity of acetic acid (0.01 mL). The reaction was heated at 85-90° C.overnight, and the solvent was removed under vacuum. The residue waspurified by silica column chromatography eluting with hexane-acetone(1:1.5) and further purified by eluting with dichloromethane-methanoland recrystallized from dichloromethane and hexane to give 203 as ayellow in overall 35% yield.

Example 17

Table 1 provides the ¹H-NMR data confirming structures of exemplarycompounds of the invention. All spectra were recorded using DMSO-d⁶ assolvent, except for compound 030 (unstable in DMSO) for which CHCl₃ wasused, at 400 MHz for all compounds, except for compounds 030 and 032 forwhich 500 MHz was used.

TABLE 1 ¹H-NMR data of exemplary compounds of the invention Cpd. No. NMR(δ ppm) 002 8.603 (t br, 1H, J = 5.62 Hz, CONH), 8.521 (s, 1H, HCO),7.550 (d, 1H, 7.57 Hz, furanH), 7.549 (s, 1H, IndH), 7.383 (dd, 1H, J1 =8.30 Hz, J2 = 5.37 Hz, indH), 7.285 (s, 1H, furanH), 7.099 (dd, 1H, J1 =9.68 Hz, J2 = 2.20 Hz, indH), 6.945 (s, 2H, PhH), 6.910 (s, 1H, ═CH),6.763 (m, 1H, furanH), 4.267 (d, 1H, J = 5.61 Hz, NCH₂), 3.767 (s, 6H,OCH₃), 3.460 (s, 2H, CH₂), 2.182 (s, 3H, CH₃) 006 8.714 (s br, 1H, OH),8.549 (t, 1H, NH), 7.480 (d, 1H, J = 8.54 Hz, FuranH), 7.071 (s, 1H,indH), 6.857 (d, 1H, J = 7.08 Hz, indH), 6.833 (s, 2H, PhH), 6.48 (d,1H, indH), 6.371 ( m, 1H, furanH) , 6.122 (m, 1H, furanH), 6.175 ( d,1H, J = 2.93 Hz, ═CH), 4.261 (d, 2H, J = 5.37 Hz, NCH₂), 3.745 (s, 6H,CH₃O), 3.707 (s, 3H, CH₃O), 3.429 (s, 2H, CH₂), 2.162 (s, 3H, CH₃) 0078.792 (s br, 1H, OH), 8.574 (t, 1H, J = 5.62 Hz, NH), 7.559 (d, 1H, J =4.88 Hz, furanH), 7.233 (s, 1H, indH), 7.084 ( dd, 1H, J1 = 9.22 Hz, J2= 2.20 Hz, indH), 6.841 (s, 2H, PhH), 6.752 (1H, m, indH), 6.481 ( m,1H, furanH), 6.322 (m, 1H, furanH), 6.205 ( d, 1H, J = 2.93 Hz, ═CH),4.264 (d, 2H, J = 6.17 Hz, NCH₂), 3.747 (s, 6H, MeO), 3.448 (s, 2H,COCH₂), 2.16 (s, 3H, CH₃) 008 8.68 (s br, 1H, OH), 8.556 (t, 1H, J =5.37 Hz, NH), 7.539 (d, 1H, J = 4.88 Hz, furanH), 7.196 (s, 1H, indH),7.088 (s, 1H, indH), 6.915 (s, 1H, ═CH), 6.846 (s, 2H, PhH), 6.37 ( m,1H, furanH), 6.198 ( d, 1H, J = 2.93 Hz, furanH), 4.264 (d, 2H, J = 5.38Hz, NCH₂), 3.752 (s, 6H, OCH₃), 3.713 (s, 3H, OCH₃), 3.493 (s, 3H,OCH₃), 3.414 (s, 2H, COCH₂), 2.16 (s, 3H, CH₃) 012 9.335 (s br, 1H, OH),8.541 ( t br, 1H, J = 5.61 Hz, CONH), 7.552 (d, 1H, J = 0.97 Hz), 7.423(d, 1H, J = 8.55 Hz, PhH), 7.106 (d, 1H, J = 1.72 Hz), 7.064 (s, 1H),6.986 (dd, 1H, J1 = 8.30 Hz. J2 = 1.47 Hz,), 6.851 (s, 1H, PhH), 6.841(d, 1H, J = 8.02 Hz), 6.480 (d, 1H, J1 = 8.58 Hz, J2 = 2.44 Hz), 6.372(dd, 1H, J1 = 2.93 Hz, J2 = 1.83 Hz), 6.197 ( d, 1H, J = 2.69 Hz), 4.254(d, 2H, J = 5.62 Hz, NCH₂), 3.748 (s,3H, CH₃O), 3.703 (s, 3H, CH₃O),3.424 (s, 2H, CH₂), 2.162 (s, 3H, CH₃) 018 10.575 (s br, 1H, NH), 9.740(s br, 1H, OH), 8.342 (t br, 1H, J = 5.37 Hz, CONH), 7.332 (d, 1H, J =8.30 Hz, indH), 7.108 (s, 2H, PhH), 7.029 (s, 1H, IndH), 6.874 (d, 1H, J= 2.27 Hz, ═CH)), 6.616 (m, 1H, PyrroH), 6.496 (dd, 1H, J1 = 8.30 Hz, J2= 2.20 Hz, IndH), 5.906 (dd, 1H, PyrroH), 5.871 (s, 1H, PyrroH), 4.188(d, 1H, J = 5.12 Hz, CONH), 3.805 (s, 3H, OCH3), 3.703 (s, 3H, OCH3),3.418 (s, 2H, CH2), 2.18 (s, 3H, CH3) 022 10.582 (s br, 1H, NH), 8.520(s br, 1H, OH), 8.342 (t br, 1H, CONH), 7.820 (s, 1H, indH), 7.276 (d,1H, J = 8.30 Hz, IndH), 6.995 (s, 2H, PhH), 6.889 (d, 1H, PyrroH), 6.620(s, 1H, ═CH), 6.519 (d, 1H, J = 8.30 Hz, IndH), 5.911 (d, 1H, PyrroH),5.878 (d, 1H, PyrroH), 4.197 (d, 1H, J = 4.87 Hz, CONH), 3.795 (s, 6H,OCH3), 3.706 (s, 3H, OCH3), 3.438 (s, 2H, CH2), 2.18 (s, 3H, CH3) 030(CDCl₃, 500 MHz) 7.4603 (d, 1H, J = 8.6 Hz, IndH), 7.0755 (s, 1H, IndH).6.7990 (s, 2H, PhH), 6.7051 (d, 1H, J = 2.3 Hz, ═CH), 6.57 (dd, 1H,IndH), 5.97 (d, br, CONH), 4.51 (m, 1H, PyrrolinH), 3.9337 (s, 3H, MeO),3.8667 (s, 6H, MeO), 3.7963 (s, 3H, MeO), 3.5066 (s, 2H, CH₂CO), 2.765(m, 1H PyrrolinH), 2.4844 (m, 1H, PyrrolinH), 2.479 (m, 1H, PyrrolinH),2.2686 (s, 3H, NCH3), 2.260 (m, 1H, PyrrolinH), 2.1770 (s, 3H, CH3),2.131 (m, 1H, PyrrolinH), 1.461 (m, 1H, PyrrolinH) 032 (500 Hz), 9.89(br, 1H, NH + Cl−), 8.189 (d, br, 1H, J = 7.45 Hz, CONH), 7.3759 (d, 1H,J = 8.6 Hz, IndH), 7.0682 (s, 1H, IndH). 6.8174 (s, 2H, PhH), 6.8170 (s,1H, ═CH), 6.57 (dd, 1H, J1 = 8.0 Hz, J2 = 2.3 Hz, IndH), 3.853 (m, 1H,CH), 3.7346 (s, 3H, MeO), 3.7048 (s, 6H, MeO), 3.6936 (s, 3H, MeO),3.344 (m, 1H, CH), 3.3693 (s, 2H, CH₂CO), 2.80 (m, 1H, CH) , 2.7314 (s,3H, NCH₃), 2.61 (m, 1H, CH), 2.1187 (s, 3H, CH₃), 1.8-1.9 (m, 2H, CH₂),1.67 (m, 1H, CH) 1.35(m, 1H, CH) 095 8.86 (br t, 1H, CONH), 7.56 (d, 1H,furanH), 7.32 (dd, 1H, indH), 7.28 (s, 1H, ═CH), 7.10 (dd, 1H, indH),6.86 (s, 2H, PhH), 6.78 (td, 1H, indH), 6.38 ( dd, 1H, furanH), 6.21 (d,1H, furan), 4.26 (q, 2H, CH₂Me), 4.23 (d, 2H, CH₂N), 3.77 (s, 6H, CH₃O),2.15 (s, 3H, CH₃), 1.26 (s, 3H, CH₃) 202 2.06 (s, 3H), 3.68 (s, 2H),3.76 (s, 6H), 4.25 (s,1H), 4.37 (d, 2H), 6.14 (d, 1H, J = 3.0), 6.36 (m,1H), 6.74 (s, 1H), 6.78 (m, 1H), 6.86 (s, 2H),7.18-7.36 (m,7H), 7.55(1H), 8.53 (1H) 203 2.06 (s, 3H), 3.68 (s, 2H), 3.76 (s, 6H), 4.25(s,1H), 4.37 (d, 2H), 6.14 (d, 1H, J = 3.0), 6.36 (m, 1H), 6.74 (s, 1H),6.78 (m, 1H), 6.86 (s, 2H),7.18-7.36 (m, 7H), 7.55 (1H), 8.53 (1H)

Example 18

This example illustrates cell growth assays employed in the presentinvention. Cells used in such assays included A-549, HT-29, MDA-MB-231,Colo-205, Caco2, HCT-116, SW-480, and DLD-1 human cancer cells obtainedfrom the American Type Culture Collection (ATCC). Human tumor cells werecultured using standard methods in RPMI-1640 growth medium supplementedwith 5% fetal bovine serum (FBS). Normal rat kidney (NRK) and Ki-Rastransformed NRK cells (K-NRK) were obtained from ATCC, and were culturedaccording to supplier recommendations. CellTiter-Glo ATP cell growthassay reagents were obtained from Promega and used according to themanufacturer's protocol. Inhibitors of EGFR, Raf, and MEK were obtainedfrom Selleck Chemicals. Cells were plated at a density of 5,000 cellsper well in 96-well microplates or 1,250 cells per well in 384-wellplates, and allowed to attach for at least 4 h. Test compounds weredissolved in dimethyl sulfoxide (DMSO), and this working stock wasfurther diluted in growth medium for addition to cell cultures. Serialdilutions of the test compound were prepared in growth medium containingan equal amount of DMSO not exceeding 0.2% final concentration. Eachcompound concentration was tested in at least 3 separate samples percell line. At the end of a 3-day treatment period, growth inhibition wasanalyzed using a bioluminescent assay of ATP concentration (PromegaCellTiter-Glo) according to the manufacturer's protocol. Resultingluminescence was measured using the luminescence cartridge of theMolecular Devices Spectramax Paradigm microplate reader. Relative growthinhibition for each sample was determined by comparison with the valuesobtained for vehicle treated control samples. Growth inhibition valueswere plotted with the GraphPad PrismS software using the 4-parameterlogistic fit to obtain IC₅₀ values, which corresponds to the growthinhibitory potency of the compound.

Example 19

Selected compounds of formula I and II were screened initially for tumorcell growth inhibition using the methods described in Example 15. Themeasured HT-29 tumor cell growth inhibitory IC₅₀ values (micromolar) forcompounds 130, 131, 132, 133, 134, 135, 138, 139, 141, 143, 144 and 145were 4.3, 2.7, 4.1, 9.3, 8.2, 0.26, 3.0, 0.49, 2.2, 1.3, 7.4 and 17.6,respectively.

Example 20

This example illustrates a Ras binding domain assay used in anembodiment of the present invention to measure Ras activation status.The activation state of Ras in cell lines was assayed using the ActiveRas Pull-Down and Detection Kit (Thermo Scientific). Cell lines werecultured as described above. Cells were disrupted with non-ionicdetergent, and the active (GTP-bound) Ras was isolated by its highaffinity for Raf via precipitate with sepharose-bound GST-Raf fusionprotein. The precipitated active Ras was then subjected topolyacrylamide gel electrophoresis (PAGE) and transferred tonitrocellulose membrane (western blot). Detection was achieved using theanti-Ras mouse primary antibody and anti-mouse-horseradish peroxidaseconjugated secondary antibody. Paired samples of whole cell lysate wereanalyzed by western blot for expression level of total Ras protein aswell as a gel loading control, glyceraldehyde 3-phosphate dehydrogenase(GAPDH). Digital enhanced chemiluminescence imaging of the resultingwestern blots was performed using a Syngene G:Box. The intensity of Rasbands from each cell line and the corresponding GAPDH bands werequantitated using NIH ImageJ, and expressed as “relative Rasactivation.”

Example 21

This example illustrates effects of exemplary compounds of the presentinvention on cancer cells having activated or mutated Ras compared towild-type (WT) Ras. Compounds were tested for their ability to inhibitthe growth of cells expressing constitutively active K-Ras oncogenecompared with cells with inactive Ras. A549 lung cancer cells, whichharbor a mutation in the K-Ras oncogene were treated for three days withthe compounds. As indicated in Table 2, the IC₅₀ values of the compoundsranged from <1 nM to over 5900 nM in cells with mutated Ras. Incontrast, when these compounds were tested for their ability to inhibitthe growth of colon cancer cells having the wild-type Ras protein(HT29), these compounds were significantly less potent, with IC₅₀ valuesranging from 280 nM to over 8000 nM. The ratio of a given compound'spotency (IC₅₀) to inhibit the growth of cells lacking activated Ras(HT-29) relative to that of cells with mutated or activated Ras (A549)demonstrates selectivity for the Ras-mutant-containing cells.

TABLE 2 Growth inhibition of cells with mutant Ras. A549 HT-29(Ras-activated) (WT Ras) Selectivity Cpd # IC₅₀ (nM) IC₅₀ (nM)HT-29/A549 001 716 6,280 9 006 11 8,130 739 007 0.86 280 326 008 1671,540 9 012 170 900 5 013 300 730 2 014 110 500 5

Example 22

This example illustrates the levels of Ras activation in differentcolorectal cancer cells. In particular, a panel of human colorectalcancer cell lines was selected to further describe the selectivity ofthe compounds for cells with activated Ras. Three of the cell lines inthe panel have been reported to harbor ras mutations: HCT-116, DLD-1,and SW-480 (Stoneman and Morris, Clin Mol Pathol., 48, M326-332 (1995)).Three of the cell lines were reported to express wild type Ras: HT-29,Caco-2, and Colo-205 (Stoneman and Morris, supra; Shirasawa et al.,Science, 260, 85-88 (1993)). The activation state of Ras in the celllines was assayed using the Active Ras Pull-Down and Detection Kit. Theratio of the intensity of the Ras to GAPDH bands was expressed asrelative Ras activation, which is presented above each lane in FIG. 4.This experiment demonstrated that the level of Ras activation inHCT-116>DLD-1≈SW-480>Caco2>HT-29>Colo205.

Example 23

This example illustrates selective growth inhibition in colorectal celllines constitutively containing activated Ras or wild-type Ras. Thegrowth inhibitory activity of the compounds was tested using theCellTiter-Glo assay. Cells were seeded in 384-well plates and allowed toattach, then ten-fold serial dilutions of compounds were tested. Eachconcentration was tested in at least 3 separate samples per cell line.As indicated in Table 3, the potency of the compounds ranged from <1 nMin cells with Ras activation, to greater than 1300 nM in cells with WTRas. The ratio of a given compound's potency ((IC₅₀) to inhibit thegrowth of cells having wild-type Ras (Caco-2) relative to that of cellshaving activated Ras (SW-480) demonstrates selectivity for theRas-mutant-containing cells.

TABLE 3 Selective growth inhibition for active Ras in a panel ofcolorectal cancer cell lines. SW-480 (Ras Caco-2 Cpd Activated) (WT Ras)Selectivity # IC₅₀ (nM) IC₅₀ (nM) Caco-2/SW-480 001 435 1,100 3 006 2.85428 150 007 0.37 1.97 5 008 139 1,330 10

Example 24

This example illustrates the correlation between the sensitivity tothese compounds and Ras activation status. The log of the IC₅₀ values offour highly active compounds were plotted on the y-axis of the graphsand the log of the relative levels of Ras activation (e.g., as describedin Example 8) was plotted on the x-axis. Linear regression analysis ofthe resulting coordinates demonstrates a statistically significantinverse correlation between Ras activation and sensitivity of the celllines as shown in FIG. 6A-6F, in which HCT-116, DLD-1, and SW-480 cellsharbor Ras mutations, while: HT-29, Caco-2, and Colo-205 expresswild-type Ras. Correlation coefficients (r²) are presented in each ofthe plots.

Example 25

This example illustrates use of well-established human colon tumor celllines with widely divergent Ras activation status to determineselectivity values for exemplary compounds of the present invention.Cell lines thus employed in this example were HCT-116, a highlyRas-driven line expressing mutant Ras, and HT-29, a non-Ras-driven lineexpressing wild-type, non-mutated Ras. Cells were plated at 5000cells/well in 96-well plates, and viable cell numbers were measuredusing the Cell Titer Glo ATP luminescence assay (Promega). FIGS. 6A-6Fshow the results of these studies for exemplary compounds 006, 007, 019,029, 002, and 022, respectively. The calculated HT-29/HCT-116selectivity values for the aforementioned compounds were 142, 290, 185,35, 116, and 117, respectively. These selectivity values are the ratiosof each compound's potency (IC₅₀) to inhibit the growth of cells lackingactivated Ras (HCT-29) relative to that of cells with activated Ras(HCT-116), demonstrating selectivity for the Ras-mutant-containingcells. Similar results were found for compounds 202 and 203, asillustrated in FIGS. 6G-6J.

This example furthermore shows that prior art studies (e.g., U.S. Pat.Nos. 6,063,818 and 6,121,321) employing individual cell lines such asHT-29 or SW-480 could not have revealed compounds with Ras-selectiveactivity useful for Ras-directed medical treatments or preventions.Employment of a cell line having normal, non-mutant Ras (e.g., HT-29)concurrently with at least one or more cell line(s) having hyperactiveor mutant Ras (e.g., HCT-116 and/or SW-480) in comparative assays oftumor cell growth inhibition are required to demonstrateRas-selectivity, and to enable selection of a Ras-inhibitory compoundnecessary for the novel methods disclosed in the present invention.

Example 26

This example illustrates non-selective growth inhibition with known Raspathway inhibitors which are not compounds of the present invention. Inparticular, the growth inhibitory activity of commercially availablecompounds which are active in the Ras signal transduction pathway weretested in the same panel of cell lines using the CellTiter-Glo assay.Cells were seeded in 384-well plates and allowed to attach. Ten-foldserial dilutions of compounds were tested. Each compound concentrationwas tested in at least 3 separate samples per cell line. As indicated inTable 4 below, the potency of the EGF receptor inhibitor compoundsranged from 4 μM to >20 μM, with no pattern of selectivity with regardto Ras activation. Likewise, the C-Raf inhibitor, GW5074, did not showselectivity for cell lines expressing activated Ras. The B-Rafinhibitors tested were generally active in the low micromolar range, butwere significantly more potent in Colo-205 cells, which have the lowestlevel of active Ras. The MEK inhibitor, Selumetinib was also most potentagainst COLO-205 and HT-29 cell lines showing, if anything, a “reverse”selectivity toward inactive Ras compared with the compounds of thisinvention.

TABLE 4 Non Ras-selective growth inhibition with known Ras pathwayinhibitors. HCT- COLO- 116 DLD-1 SW-480 Caco-2 HT-29 250 IC₅₀ IC₅₀ IC₅₀IC₅₀ IC₅₀ IC₅₀ Compound Target (nM) (nM) (nM) (nM) (nM) (nM) GefitinibEGFR 12,600 7,550 8,630 8,920 6,370 8,200 GW5074 C-Raf 15,800 7,7508,070 >20,000 19,100 7,100 GDC0879 B-Raf 8,140 7,640 >20,000 >20,00023,600 75.8 Vemurafenib B-Raf 5,990 5,620 6,860 5,200 5,100 151Selumetinib MEK 4,110 20,400 >20,000 >20,000 854 4.60

Together, these data demonstrate the activated Ras selective growthinhibitory activity of the compounds of this invention. This is incontrast to the current clinically used inhibitors of proteins withinthe Ras signaling cascade that exhibit no selectivity or selectivity forcells lacking activated Ras.

Example 27

This example illustrates the treatment of a mammalian patient with acompound of the present invention. The antitumor activity of compound030 (specifically the S-enantiomer thereof) was evaluated in anorthotopic mouse model of lung cancer utilizing human A549 lungadenocarcinoma cells. Toxicity and efficacy were assessed by determiningtreatment effects on weight gain and by necropsy observations. Treatmenteffects on tumor growth in live mice were also measured with human A549lung adenocarcinoma cells that were engineered to contain a luciferaseexpression vector using an In Vivo Imaging System (IVIS). In brief,female athymic nude-Foxn1^(nu) mice, 6-7 weeks old were randomly dividedinto two groups that were treated with either vehicle (Maalox®) orcompound 030 (100 mg/kg). Each group contained 15 mice in which 10 wereimplanted with non-luciferase A549 cells and 5 were implanted withluciferase A549 cells. Treatment was initiated 5 days before implantingtumor cells and was administrated to both groups by gastric gavage twicea day. For tumor cell implantation, cultured luciferase ornon-luciferase human A549 lung tumor cells were collected and mixed withequal volume of Matrigel at a final concentration of 0.250 mg/mL. Themice were weighed and anesthetized and a mark placed on the skin at thelateral dorsal line, approximately 1.5 cm above the lower rib line justbelow the inferior border of the scapula. A pre-cooled 0.5 mL insulinsyringe with a permanently attached 28 G needle was loaded with 75microliters of a cell suspension containing one million cells andinserted at the mark to a depth of approximately 5 mm. Body weight wasmeasured twice a week and IVIS imaging one done once a week. All of themice treated with compound 030 survived for the duration of theexperiment, while one mouse in the vehicle group died.

FIG. 7A shows the effect of treatment on body weight for the duration ofthe experiment. Relative to the mice treated with vehicle group, themice treated with compound 030 showed increased weight gain,demonstrating that the compound was not overtly toxic and that micetreated with 030 were in better health compared with mice treated withvehicle only. FIG. 7B shows the results from grading at necropsy inwhich 2 of 10 mice treated with 030 showed no tumors on the lung orchest cavity, 7 of 10 showed no tumors on the lung but having tumors inthe chest cavity, and 1 with tumors on the lung and in the chest cavity.By comparison, 9 of 10 mice treated with vehicle showed tumors on thelung and chest cavity including 2 having lung effusions as well. FIG. 7Cshows the effect of treatment with compound 030 on tumor growth in livemice over the duration of the experiment as measured by luminescence.

Example 28

This example, which describes an investigation employing geneticallyengineered isogenic tumor cell lines, shows confirmation of Rasselectivity of an exemplary compound of the present invention. In onestudy, human colon HT29 tumor cells were transfected with retroviralmutant H-Ras-G12V (H-Ras^(m)) or retroviral control (Retro) and stableclones were selected by puromycin. The cell lines, including parentallines (Par) were treated with compound 007 (ADT-007) for 72 hours andviable cell numbers were measured using the Cell Titer Glo assay. Raspull-downs were performed with GST-RBD-C-Raf kits (ThermoSci) followingcell extraction and detected by Ras antibody on Western-blots for theamount of active GTP-Ras. Total Ras levels among these cell extractionswere detected by the same Ras antibody. Results shown in FIG. 8Ademonstrate that the cells transfected with activated Ras werehypersensitive to the test drug (007) relative to the respective controlcells. In another study human lung H322 tumor cells were stablytransfected with retroviral mutant H-Ras-G12V (H-Ras^(m)) or retroviralcontrol (Retro). Cell lines, including parental lines (Par) were treatedwith compound 007 (ADT-007) for 72 hours and viable cell number measuredusing the Cell Titer Glo assay. Ras pull-downs were performed withGST-RBD-C-Raf kits (ThermoSci) following cell extraction and detected byRas antibody on Western-blots for the amount of active GTP-Ras. TotalRas levels among these cell extractions were detected by the same Rasantibody. Results shown in FIG. 8B demonstrate that the cellstransfected with activated Ras were hypersensitive to the test drug(007) relative to the respective control cells.

Example 29

This example illustrates that representative Ras-inhibitory compounds ofthe present invention interact with high affinity directly withactivated Ras to disrupt Ras interactions with a normal binding partner.In particular, this study shows (FIG. 9) disruption of Ras-Raf bindingby compound 007 (ADT-007) and compound 006 (ADT-006). Inhibition studiesof Ras binding to Raf by treatment with Ras inhibitors using a Rafpull-down assay was conducted in vitro in cell lysates (FIG. 9, toppanel) or in intact cells (FIG. 9, bottom panel). For in vitroexperiments, whole cell lysates from human H322 lung tumor cellstransfected with activated (mutant) H-Ras were incubated for 30 minutesat room temperature with 007 or 006 at the designated concentrations.GTP-bound (active) Ras was precipitated with GST-Raf1-RBD/GSH Sepharose(Thermo Scientific) and detected by western blotting. Numerical valuesbelow the blots show the quantification of Ras protein by densitometry.As a positive control, lysates were incubated with 5 mM GDP todeactivate Ras. For experiments involving intact cells, the same methodas described above was used except intact H322 lung tumor cells wereincubated with 007 for 1 hour at 37° C. prior to the Raf pull-downassay.

Example 30

This example illustrates that administration of therapeutic orpreventive doses of representative compounds used in the presentinvention produced no evidence of in vivo animal toxicity as assessed byanimal weight gains over time. Female athymic Nude-Foxn1^(nu) mice, 6-7weeks old were purchased from Harlan and acclimated for 1 week. Mice hadaccess to water and food ad libitum for the duration of the experiment.HCT-116 cells were cultured under optimal conditions (RPMI media, 5%fetal bovine serum, antibiotics, glutamate at 5% CO₂ and 36° C.). On theday of inoculation, cells were collected from flasks 70-80% confluent.Mice were inoculated with 5×10⁶ cells/100 μL in the right flank and10×10⁶ cells/100 μL in the left flank. Compounds 006, 011 and 019(identified in FIG. 10 as ADT-006, ADT-011, and ADT-019, respectively)were administered twice daily by ip injection for 14 days at a dosage of5 mg/kg. Compound 007 (identified as ADT-007 in FIG. 10) wasadministered in a similar manner except at a dosage 2.5 mg/kg. Thevehicle for all compounds contained ethanol, polyethylene glycol-300,and water at a ratio of 5:75:20. Percent body weight change of micetreated with vehicle alone or with vehicle with test compounds relativeto the body weight of the mice prior to treatment is shown. No change inbody weight is shown as 100%. Error bars represent standard errors ofthe means. While there were some minor differences in animal weightsearly in the experiment, the drug-treated animal weights werestatistically indistinguishable from controls for the duration of theexperiment, indicating little if any toxic effects of any of the testdrugs that would otherwise be manifest as significant body weightchange.

Example 31

This example illustrates efficacious therapeutic antitumor treatments(FIGS. 11A-D) of a representative Ras-driven tumor in vivo withexemplary Ras-inhibitory compounds of the present invention. Femaleathymic Nude-Foxn1^(nu) mice, 6-7 weeks old were purchased from Harlanand acclimated for 1 week. Mice had access to water and food ad libitumfor the duration of the experiment. HCT-116 cells were cultured inoptimal conditions (RPMI media, 5% fetal bovine serum, antibiotics,glutamate at 5% CO₂ and 36° C.). On the day of inoculation, cells werecollected from flasks 70-80% confluent. Mice were inoculated with 5×10⁶cells/100 μL on the right flank. Treatment was initiated once tumorsreached an average size of 50 mm³. Compounds 006, 011 and 019(identified in FIGS. 11A, 11C and 11D as ADT-006, ADT-011, and ADT-019,respectively) were administered twice daily by ip injection for 14 daysat a dosage of 5 mg/kg. Compound 007 (identified in FIG. 11B as ADT-007)was administered in a similar manner except at a dosage 2.5 mg/kg. Thevehicle for all compounds contained ethanol, polyethylene glycol-300,and water at a ratio of 5:75:20. Error bars represent standard errors ofthe means at each point, and analysis of variance showed that the growthcurves of drug-treated animals versus vehicle-only control animals werehighly statistically different. Namely, the results shown in FIGS. 11A-Ddemonstrate that all four compounds profoundly suppressed tumor growth;in fact, in this study there were multiple “cures” in each drug-treatedgroup (i.e., animals were completely free of macroscopically visibletumor at the end of the experiment). Another study, results of which areillustrated in FIGS. 11E-H, employed a “prevention” protocol rather thana “therapeutic” protocol. Female athymic Nude-Foxn1^(nu) mice, 6-7 weeksold were purchased from Harlan and acclimated for 1 week. Mice hadaccess to water and food ad libitum for the duration of the experiment.HCT-116 cells were cultured in optimal conditions (RPMI media, 5% fetalbovine serum, antibiotics, glutamate at 5% CO₂ and 36° C.). On the dayof inoculation, cells were collected from flasks 70-80% confluent. Micewere inoculated with 10×10⁶ cells/100 μL on the left flank, andtreatment was initiated one day following tumor implantation. Compounds006, 011 and 019 (identified in FIGS. 11E, 11G and 11H as ADT-006,ADT-011, and ADT-019, respectively) were administered twice daily by ipinjection for 14 days at a dosage of 5 mg/kg. Compound 007 (identifiedin FIG. 11F as ADT-007) was administered in a similar manner except at adosage 2.5 mg/kg. The vehicle for all compounds contained ethanol,polyethylene glycol-300, and water at a ratio of 5:75:20. Treatment wasinitiated one day following tumor implantation. Error bars representstandard errors of the means at each point, and P-values are derivedfrom analysis of variance which showed that the growth curves ofdrug-treated animals versus vehicle-only control animals were highlystatistically different. Namely, the results shown in FIGS. 11E-Hdemonstrate that all four compounds profoundly prevented tumor growth.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing the invention (especiallyin the context of the following claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The use of the term “at least one”followed by a list of one or more items (for example, “at least one of Aand B”) is to be construed to mean one item selected from the listeditems (A or B) or any combination of two or more of the listed items (Aand B), unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

The invention claimed is:
 1. A compound, (Z)- or (E)-isomer thereof, offormula IIa:

wherein: R₁, R₂, R₃, R₄, R₁₃ and R₁₅ are independently selected fromhydrogen, halogen, alkyl, cycloalkyl, haloalkyl, and alkoxy; R₇ and R₈are independently selected from hydrogen, alkyl, haloalkyl and alkoxy;R₁₄ is of the formula Q-U— wherein U is selected from the groupconsisting of oxygen, sulfur, OCH₂, SCH₂ and NHCH₂; and Q is selectedfrom the group consisting of PEG-CO, amino acid, substituted benzoicacid and phosphoric acid; or, wherein Q-U together is a substituted orunsubstituted group selected from phosphonooxy, phosphonoalkyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy; R′ is selected from furanyl andfuranylalkyl wherein the furanyl of the furanyl and furanylalkyl isoptionally substituted with one or more of halo, alkyl, haloalkyl,hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto,alkylmercapto, carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, andsulfonamido; or, a pharmaceutically acceptable salt thereof.
 2. Thecompound, (Z)- or (E)-isomer thereof, or a pharmaceutically acceptablesalt thereof, of claim 1, wherein R₁₄ is a substituted or unsubstitutedgroup selected from phosphonooxy, phosphonoalkyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy.
 3. The compound, (Z)- or (E)-isomerthereof, or a pharmaceutically acceptable salt thereof, of claim 2,wherein R₁₄ is a substituted or unsubstituted group selected fromphosphonooxy, phosphonoalkyloxy, arylcarbonyloxy, arylalkylcarbonyloxy,aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy.
 4. The compound, (Z)- or (E)-isomerthereof, or a pharmaceutically acceptable salt thereof, of claim 3,wherein R₁₄ is a substituted or unsubstituted group selected fromphosphonooxy, phosphonoalkyloxy, arylcarbonyloxy, arylalkylcarbonyloxyand aryloxycarbonyloxy.
 5. The compound, (Z)- or (E)-isomer thereof, ora pharmaceutically acceptable salt thereof, of claim 1, wherein R′ isfuranylalkyl optionally substituted with one or more of halo, alkyl,haloalkyl or alkoxy.
 6. The compound, (Z)- or (E)-isomer thereof, or apharmaceutically acceptable salt thereof, of claim 5, wherein thefuranylalkyl is unsubstituted.
 7. The compound, (Z)- or (E)-isomerthereof, or a pharmaceutically acceptable salt thereof, of claim 1,wherein R₁, R₂, R₃ and R₄ are independently selected from hydrogen,halogen, alkoxy, alkyl, and haloalkyl.
 8. The compound, (Z)- or(E)-isomer thereof, or a pharmaceutically acceptable salt thereof, ofclaim 7, wherein R₁, R₃ and R₄ are each hydrogen.
 9. The compound, (Z)-or (E)-isomer thereof, or a pharmaceutically acceptable salt thereof, ofclaim 8, wherein R₂ is fluoro.
 10. The compound, (Z)- or (E)-isomerthereof, or a pharmaceutically acceptable salt thereof, of claim 1,wherein R₇ is hydrogen and R₈ is alkyl.
 11. The compound, (Z)- or(E)-isomer thereof, or a pharmaceutically acceptable salt thereof, ofclaim 1, wherein R₁, R₂, R₃ and R₄ are independently selected fromhydrogen, halogen, alkoxy, alkyl and haloalkyl; R₇ is hydrogen; and R₈is alkyl.
 12. The compound, (Z)- or (E)-isomer thereof, or apharmaceutically acceptable salt thereof, of claim 1, wherein R₁, R₃ andR₄ are each hydrogen; R₂ is selected from halogen and alkoxy; R₇ ishydrogen and R₈ is alkyl; and R₁₃ and R₁₅ are each alkoxy.
 13. Thecompound of claim 1, which is selected from:(Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylbenzoate,(Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl(4-nitrophenyl) carbonate,(Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylbenzoate,(Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylnicotinate,(Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyldihydrogen phosphate,(Z)-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyldihydrogen phosphate,(Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylnicotinate,(Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl(4-nitrophenyl) carbonate,(Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyldihydrogen phosphate, and(Z)-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)methyldihydrogen phosphate, or the corresponding (E)-isomer thereof, orpharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a compound, (Z)- or (E)-isomer thereof, or apharmaceutically acceptable salt thereof, of claim 1, and apharmaceutically acceptable carrier.
 15. A method of therapeuticallytreating a human or nonhuman mammalian patient having cancer, whereinthe cancer is selected from pancreatic cancer, lung cancer, colorectalcancer, melanoma, ovarian cancer, renal cancer, prostate cancer, headand neck cancer, endocrine cancer, uterine cancer, breast cancer,sarcoma cancer, gastric cancer, hepatic cancer, esophageal cancer,central nervous system cancer, brain cancer, hepatic cancer, germlinecancer, lymphoma, and leukemia, comprising administering to said patientan anticancer effective amount of at least one compound, (Z)- or(E)-isomer thereof, or a pharmaceutically acceptable salt thereof, ofclaim 1, wherein said at least one compound, (Z)- or (E)-isomer thereof,or a pharmaceutically acceptable salt thereof is administered alone orin combination with an antitumor drug or radiation, wherein saidantitumor drug is not a compound, (Z)- or (E)-isomer thereof, or apharmaceutically acceptable salt thereof, of claim 1.